Forest's resounding win left the club in eighth place, just one point adrift of the Championship play-off places.
But it was not enough to save O'Driscoll, who left Crawley in the summer to take over at the City Ground, and Forest are now targeting a replacement with Premier League experience.
Reds chairman Al Hasawi told club's official website: "The timing of our decision may look a little odd after the win over Leeds but sometimes you need to make changes with the long-term future in mind.
"Sometimes those changes need to be made from a position of strength rather than weakness and that is what we are trying to do.
"We are looking to bring in an ambitious manager with Premier League experience."
Al Hasawi admitted the decision was tough on O'Driscoll.
He said: "We cannot speak highly enough of Sean as a man.
"He was appointed at an extremely difficult time for the club and can count himself unlucky to have lost his job with the team just one point away from the top six.
"But we have a responsibility to look to the future for this great club because we have huge ambitions for it.
"We knew when we bought the club in the summer that it would take time for the players we bought in to settle but that process has taken longer than we anticipated.
"We feel we have developed a really strong squad of players but are still searching for consistency in terms of team performance, underlined by the fact that we have not won more than two games in succession in the Championship this season.
"And with the January transfer window approaching, we feel it's the right time to make a change."
The statement concluded: "The club will be making no further comment at this time."
Forest striker Billy Sharp, who turned the match against Leeds around with two goals, responded to O'Driscoll's shock departure by tweeting: "gutted that ruins a decent day".
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