The defending champions, back at the game's headquarters for the first time since their title win over Leicester in May, allowed Wasps to come from behind and take the win with a late Tom Varndell try.
The defeat continued a curse for any side defending its title, with Saracens becoming the ninth team to suffer an opening-fixture loss in 11 years.
Despite the summer signing of Sale legend Charlie Hodgson, Saracens started with teenager Owen Farrell at fly-half.
In opposition, Wasps gave debuts to five players - Hugo Southwell, Chris Bell, Nicky Robinson, Marco Wentzel and Jonathan Poff - while Riki Flutey made it clear pre-match that he was determined to prove England manager Martin Johnson wrong for leaving him out of the World Cup squad.
But it was Farrell who drew first blood, kicking a seventh-minute penalty at the end of sustained pressure, and adding another two minutes later for offside in front of the posts.
Wasps took a while to settle, but won a penalty off the game's first scrum, kicked by former Wales fly-half Robinson after 16 minutes, and that gave them a second gear.
Saracens were then carved open for a splendid try on 20 minutes.
A sweeping crossfield move peaked with brilliant hands by Flutey to Bell who armed Christian Wade to escape the cover and score on the right.
Saracens prevented further damage under testing pressure before regaining their earlier control, and a searing break by David Strettle required two defenders to halt.
The form of Poff and Bell will have delighted Wasps as much as it alarmed the champions during a half they began by dominating yet finished in arrears.
Wasps struggled to secure possession at a breakdown and conceded a penalty kicked by Farrell to reduce the arrears to one point.
But Bell won Wasps the last kick of the half. His break led to a ruck, former England captain Steve Borthwick came in from the side and Robinson made it three kicks from three.
Saracens were given the opportunity to regain the lead two minutes into the second half when Charlie Davies was penalised for not releasing, but Farrell's penalty sailed wide.
Then, when Mouritz Botha fumbled at the back of a ruck, Joe Launchbury hacked on, and, although Alex Goode won the chase, he then made the mistake of trying to dummy the flanker under his posts and was driven over his line.
It was danger time for Saracens, but Wasps allowed them to get a powerful surge on and the ball squirted out the back.
The next scrum was 15 metres out rather than five, and the chance was lost totally when Davies delayed at the put-in.
Hodgson made his Saracens debut on the 50th minute, replacing Farrell, and his first contribution was to take the side forward.
Wasps held out under intense pressure, but Saracens looked certain to score when Goode found Ernst Joubert feet from the line and unopposed. Varndell got the slightest of touches when the ball was in flight, however, and it was just enough to deflect it away from the forward's fingers.
Hodgson did mark his debut with points on 56 minutes, a penalty awarded when Wasps failed to roll away after tackling at the breakdown.
And he was fully into his stride four minutes later, nudging his new club back in front with a second goal. But not for long.
Wasps turned over Jackson Wray on the left, Davies broke and when former England wing Varndell took his pass, two Saracens defenders failed to halt his determined surge for the line.
Robinson converted, before Hodgson got the chance to make it a hat-trick of goals eight minutes from time, but hooked his attempt from wide left of the posts.
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