First-half goals from Victor Moses and Diafra Sakho gave the Hammers - who had already beaten Arsenal and Liverpool away this season - a shock 2-0 lead.
Kevin De Bruyne threw the hosts a lifeline by reducing the arrears before the break, but it proved a false dawn as United held strong throughout a one-sided second period to pick up a hat-trick of unlikely away wins.
Below, relive the scalp with our live text commentary.
Ordinarily, West Ham United's trip to Manchester City would take on a David versus Goliath feel. But not when David has been KO'ing every mountain of a man that has stepped in his path in the lead up to such a seemingly one-sided contest. This, potentially, could be about as one-sided as a ruddy rubix cube. I'm Shane and I'll be bringing you all the action from Eastlands as the Sky Blues look for a sixth straight Premier League win to preserve their perfect start but, with West Ham specialising in high-profile away wins as of late, nothing is certain.
Indeed, with victories at Arsenal and Liverpool under his belt, Slaven Bilic, in his first season as Hammers boss, brings his boys to the Etihad looking to complete the hat-trick of unlikely away victories. Just ask Arsene Wenger - maybe in, say, four hours, because he might be a little hot under the collar now - or Brendan Rodgers if it is easy to beat United. They won 2-0 at Arsenal on the opening day, before smashing Liverpool 3-0 at Anfield last month.
That being said, Manchester City, as it stands, are on another level to practically every other side in the division. Five wins. Eleven scored. Zero conceded. Manuel Pellegrini's men have been flawless in every way and if West Ham are to maintain their capacity to shock the big boys, they'll have to work hard. Very, very hard.
On that note, shall we take a quick look at the team news? Okay, but first, take a mosey on down to Sports Mole HQ to see how the lads view this one and I'll see you in a few short minutes. Go on.
Let's start with Pellegrini and co. The Chilean manager has the luxury of recalling Sergio Aguero to the side after injury caused him to miss out on a starting berth in the 2-1 defeat by Juventus in the Champions League. There's no shortage of talent behind him as Kevin De Bruyne, David Silva, Raheem Sterling and Yaya Toure all start! What a ridiculous midfield. On a negative note, Vincent Kompany drops through injury as Nicolas Otamendi comes in to partner Eliaquim Mangala.
On to West Ham, who make three changes from their 2-0 win over Newcastle on Monday. Corporal Carl Jenkinson comes in to replace the injured Angelo Ogbonna, with James Tomkins moving to centre-back to partner Winston Reid. Pedro Obiang shrugs off an injury to start and displace Cheikhou Kouyate, while Adrian returns from suspension to replace Darren Randolph between the sticks. Dimitri Payet, very much their star of the season so far, starts of course.
DID YOU KNOW? Citeh have won their last seven home visits of West Ham United? Yep. It's fairly formidable. That being said, United did win 2-1 at City - albeit at Maine Road - in the FA Cup back in 1998. Steve Lomas scored the winner against his former club that day.
Try telling West Ham fans they can't win this evening. Just try it! They'll have two words for you, the first of which I can't say but it probably begins with F.
Prediction : Man City 1-2 West Ham
— West Ham Stuff ⚒ (@WestHamStuff) September 19, 2015
Angelo Ogbonna, absent today with injury, is with his teammates in spirit as he urges them to repeat their scalps of the Emirates and Anfield.
So bad not being there! Good luck guys! I want you as when you were at the Emirates and Anfield Road!👊🏿👊🏿 #GoHammers#MCIWHU#WHUFC
— Angelo Ogbonna (@OgbonnaOfficial) September 19, 2015
Hmm, this is a blow for City as David Silva pulls out with injury. Shame. I was quite looking forward to seeing him, De Bruyne and Sterling tucked in behind Aguero. Ridiculous on paper, isn't it? Anywho, we won't be seeing that quartet today.
Anywho, join us in just five minutes times as the Sky Blues look for a sixth successive league win. West Ham might have something to say about that, mind.
Diafra Sakho gives Mangala a bit of bother early doors but City eventually clear. This could be a cracker. We've already see one high-profile game be shrouded in controversy, with Chelsea's win over Arsenal, but hopefully this wins headlines for the right reasons.
SAVE! We've seen our first sight of De Bruyne, who runs on to Sagna's ball before drilling it into the box, but Winston Reid clears. From the corner, Mangala's header is straight at Adrian and West Ham clear.
Oh my word. This was not in the script. Victor Moses is given far too much space outside the box, and Mangala's closing down is nothing short of pathetic, and the Chelsea loanee makes him pay dearly with a fine bullet of as a strike past Joe Hart at his near post. Very, very interesting start to this one.
CHANCE! Good lord. Does Adrian think he's Usain Bolt? He comes racing out of his goal in a 50-50 with Aguero, who obviously wins, but he pulls his effort wide after a couple of West Ham players obscured his route to goal. Good response by City.
Yaya Toure swings in a wonderful cross, but Sterling's first touch is dodgy and West Ham clear. Why he didn't just swing a boot at it I'm not too sure.
City been utterly dominant since falling behind, but West Ham doing well to shackle their heavy hitters, with the likes of Navas, Sterling and De Bruyne practically non-existent so far.
'Come on City' echoes around the Etihad as they bid to become a 12th man, but it's proving futile thus far. Dare I suggest that West Ham look comfortable back there?
Massive block from Otamendi. Huge. Mangala slid in and missed his challenge with Jenkinson, who drilled a low cross into the box as Sakho waited to pounce, but the Argentine new boy averted the danger. He spared Mangala's blushes big time.
You know what, it's not beyond the realms of possibility for West Ham to score again. Mangala looks an utter mess back there. I really wouldn't be surprised to see Demichelis.
This is bizarre. Utterly, utterly bizarre. Winston Reid rises highest to meet Payet's corner. The ball drop to Sakho, who shrugs off post man Fernandinho before scuffing the ball home from close range. City look so suspect at the back without captain and leader Vincent Kompany.
If you needed any more proof that Aguero wasn't at the races then get this - he runs through on goal before volleying well over the bar. He was offside, but he still fired the ball out of the stadium. And probably out of this stratosphere. He owes Russia a satellite.
CLOSE! Aguero drops the shoulder to deceive his marker before curling wide, moments after Navas's first-time effort was parried by Adrian. You get the feeling City need to score before the break. West Ham look resolute.
CHANCE! City piling on the pressure, as Aguero looks to flick home Navas's cross but Adrian is on hand to deny the Argentine with a double save. Good goalkeeping.
HUGE! Mangala atones for a few dodgy errors with a crucial, goal-saving tackle to deny Sakho, who shrugged off a challenge from Kolarov. City look all over the place back there.
Game on at the Etihad and what a massive, massive one it could prove to be. Aguero lays it off to the Belgian, whose first touch is perfect, and his second is even better as he drills past Adrian from outside the box. Huge goal.
Not in the script? You can say that again.Victor Moses drilled them into a 1-0 lead, before Diafra Sakho doubled the advantage with a scrappy goal from a corner. It could, and would, have been three if not for Eliaquim Mangala, who atoned for a few earlier errors by taking the ball of Sakho's toe just as he went to pull the trigger. It was crucial, as Kevin De Bruyne then reduced the arrears before the break with a superb finish as he threw his new side a huge lifeline.
KICKOFF: And we're back underway at the Etihad, my friends. Will De Bruyne's effort just before the break prove the foundations for a comeback? Time will tell.
SHOT! Immense pressure? That's an understatement. Toure looks certain to volley home from close range after Adrian flapped at a Navas ball, but Tomkins, I think, pulled off an excellent block.
Sterling plays in Toure, who bursts through United's defence like a freight train but Adrian is out brilliantly to smother the ball. Slowly but surely, big Yaya is becoming more influential.
Brilliant defending from Reid, who has been superb today. He blocks off Aguero legitimately after the Argentine telegraphed his intentions somewhat. He wants a penalty but no chance.
CLOSE! So, so, so close from Toure, who skips past Obiang far too easily before drilling inches wide of Adrian's post from the right-hand side. The big Ivorian is getting closer.
SAVE! Adrian pulls off two fine stops as Man City pile the pressure on again. Kolarov's near-post cross is flicked goalward by Aguero, before Navas's cross is turned behind. It's kitchen sink stuff.
Twenty minutes to go then and Demichelis almost thumps home an equaliser but the corner goes over his head. Plenty of noise now as City fans urge on their troops.
PENALTY APPEAL! Man City want a penalty after Sakho brings down Kolarov in the box, but it's never in a million years a penalty. Fifteen minutes to go!
This place is like a scene from The Grey now - no wolves, but A LOT of whistling. City fans aren't happy with Carl Jenkinson, who is receiving treatment. Rather cynically, they think it's a time-wasting ploy, but he looked in genuine pain.
West Ham just getting a bit of respite now. If they hold off and win here then, well, what a phenomenal defensive achievement it'll prove. Ten to play.
Superb from Noble as he throws himself in the line of fire to block Toure's stinging shot. That sums up West Ham this evening. Each of them to a man have been sublime.
City, as you might expect, are camped in West Ham's half. Bilic looks a little like Broadie from Homeland in that scene in the war bunker. He's sweating, tugging at his collar. He's got two minutes left before a huge win!
Wow. Just wow. They beat Arsenal and Liverpool but people said this was different. Is it heck! West Ham end Manchester City's perfect - and we do mean absolutely flawless - start to the Premier League season with a 2-1 win at the Etihad. First-half goals from Moses and Sakho did the damage, with De Bruyne then reducing the arrears before the break, but a herculean defensive effort saw them earn a second-half clean sheet. Wow. Take a bow Mr Bilic.