The decision was taken after the Chairboys' latest defeat left them 21st in the table, with just four points from seven matches.
Waddock led the club to promotion from the basement division in the 2010-11 campaign but they were relegated at the end of last season.
A statement from Wycombe read: "Manager Gary Waddock has been relieved of his duties with immediate effect. The club would like to thank Gary for his efforts during his time at the club and wish him every success for the future. A further statement will be made on Monday.
Earlier, in the immediate aftermath of the match, Waddock conceded his future was out of his hands.
"The players have let the club down, they've let themselves down and let me down," he said. "I don't make the decisions about my future, so I can only comment on the game. I'm a determined character, I'll always give 100 per cent and I'll work as hard as I possibly can to turn it around."