With three games in the space of seven days, Tottenham boss Martin Jol knew his squad was going to be tested to the maximum and he made three changes from the side that beat Charlton 2-0 at The Valley on Monday night.
Anthony Gardner, Steed Malbranque and Defoe were all recalled to the starting line-up as Jermaine Jenas and Ricardo Rocha failed to overcome knocks.
Tottenham came close to opening the scoring on 24 minutes when Aaron Lennon used all his pace to burst past Christopher Samba down the right-hand side.
The England winger crossed in for Gardner, who had made a surging run into the penalty box, but the Spurs defender directed his header straight at Brad Friedel in the Blackburn goal.
Spurs suffered a major injury blow on the half-hour mark when Malbranque was forced to leave the field following a crunching challenge with Aaron Mokoena.
And they were made to pay when Blackburn took the lead on 32 minutes.
Morten Gamst Pedersen's left-foot cross picked out McCarthy, who flashed a close-range header past Paul Robinson into the corner of the net.
Jason Roberts could have made it two for Rovers just 60 seconds later when his shot deflected off Michael Dawson, but Robinson made a fine save diving low to his right.
Tottenham substitute Hossam Ghaly infuriated the home supporters when he was replaced by Robbie Keane on the hour-mark and ripped his shirt off and threw it past Jol in the dug out.
Blackburn should have doubled their lead on 62 minutes when Pedersen's free-kick picked out McCarthy but his header cannoned back off the crossbar.
But Tottenham's persistence paid off and Defoe grabbed a vital equaliser on 67 minutes.
Dimitar Berbatov produced a clever turn inside the box and saw his cross spilled by Friedel. The rebound fell perfectly to Defoe, who made no mistake sliding the ball into an empty net.
Keane blew a golden chance to win the game in injury time when he broke free inside the box, but saw his shot come back off the post.
Blackburn striker Roberts was later shown the red card for two bookable offences and his side will now need to rely on the Intertoto route if they are to play in the UEFA Cup.