Hamburg SV beat last season's runners-up Schalke 04 2-1 thanks to two goals by Dutch forward Ruud van Nistelrooy.
On Friday, champions Bayern Munich needed a stoppage-time goal from Bastian Schweinsteiger to beat VfL Wolfsburg 2-1.
Werder, hoping to qualify for the Champions League group stage after beating visitors Sampdoria 3-1 in the first leg of their midweek play-off, had taken a third-minute lead with a penalty from captain Torsten Frings awarded for handball.
Hoffenheim then burst into life, netting four times through Demba Ba, teenager Peniel Mlapa, Vedad Ibisevic and a well-struck Sejad Salihovic free kick as their opponents imploded on the first full match day of the season.
Werder, who sold top midfielder Mesut Ozil to Real Madrid in the week, made a good start but instead of building on their lead they conceded too much space to the hosts and no one stepped in to fill the playmaking void.
It came as no surprise when Ba equalised in the 20th minute, pouncing on a poor clearance of Ibisevic's cross to slot home from close range.
The 19-year-old Mlapa then fired the hosts into the lead as he raced clear to beat keeper Tim Wiese in the 37th minute before Ibisevic and Salihovic added two more goals.
"The team remained calm (after the penalty). So to lead at half-time 4-1 is just fantastic," said Hoffenheim coach Ralf Rangnick.
VAN NISTELROOY BRACE
Van Nistelrooy made a sparkling start to the Bundesliga season, volleying Hamburg into the lead right after half-time.
Playing against his former Real Madrid team mate Raul, who was substituted in the second half, the Dutch striker also rattled the bar with a free-kick.
Hamburg were dominant against 10-men Schalke after Benedikt Hoewedes was sent off but they failed to kill off the game, squandering several good chances.
Hamburg were seemingly punished for their careless finish when Jefferson Farfan spectacularly flicked in an Ivan Rakitic free kick to level in the 80th minute but Van Nistelrooy tapped in a Ze Roberto pass only three minutes later for the winner.
Promoted Kaiserslautern and St Pauli had perfect starts with 3-1 wins at Cologne and Freiburg respectively.
Hanover 96 put their first-round German Cup exit last week behind them to edge Eintracht Frankfurt 2-1.
