The Tottenham strike pairing have been a revelation for Martin Jol's side this season and they proved the difference once again in helping Spurs prepare for another European adventure.
Although Emile Mpenza pulled a goal back for Manchester City just before half-time, strikes from Keane and Berbatov ensured Tottenham picked up all three points at White Hart Lane.
Keane fired Tottenham into the lead on ten minutes. Jermaine Jenas played a clever chip into the box and the Republic of Ireland striker broke the offside trap and fired a volley through the legs of Andreas Isaksson in the City goal.
Tottenham keeper Paul Robinson showed once again why he is England's number one when he made a superb save to deny Darius Vassell on 21 minutes.
Richard Dunne's cross picked out the City striker whose close-range shot was tipped away by Robinson diving away to his left.
Manchester City suffered a major injury blow on 28 minutes when Sylvain Distin was forced to leave the pitch and was replaced by Dietmar Hamann.
And they were made to pay when Berbatov added a second for the home side on 32 minutes.
The Bulgarian international caused all kinds of problems for the City defence on the edge of the box before striking a low drive past Isaksson onto the corner of the net.
City refused to lie down and forced their way back into the game on 40 minutes.
Hamann's cross picked out Mpenza who was totally unmarked inside the box and he flashed a close-range header past Robinson.
City blew a golden chance to snatch an equaliser just two minutes later when Mpenza's shot was only parried by Robinson.
The rebound fell nicely to Michael Johnson, but with the goal at his mercy he directed his header over the bar.
Robinson came to Tottenham's rescue once again on 57 minutes. DaMarcus Beasley's cross fell to Mpenza whose header looked destined for the top left-hand corner.
But Robinson showed all his class to tip the ball around the post and deny the Belgian striker.
Tottenham were awarded a controversial penalty on 85 minutes when Didier Zokora was allegedly brought down by Dunne.
But substitute Jermain Defoe saw his spot kick saved by Isaksson and then fired the rebound over the bar.