Jesualdo Ferreira's Panathinaikos went ahead after 14 minutes through in-form Portuguese midfielder Zeca and Brazilian forward Cleyton doubled the advantage a minute after half-time.
OFI's Serbian midfielder Zeljko Kalajdzic reduced the deficit with a 58th-minute penalty but Panathinaikos top scorer Sebastian Leto netted his 11th goal of the season, also from the penalty spot, with 15 minutes left to seal the club's seventh win in nine games.
The result moved the unbeaten Greens on to 23 points from nine matches, one point ahead of AEK Athens who have played two games more.
"All the matches are difficult but we are training well and winning games, a combination which is giving us even more confidence. This win brings us closer to the title," Zeca told reporters.
Twenty-four hours earlier AEK went top of the table for the first time in over three years after a 2-0 win over Panetolikos thanks to two goals from Cameroon striker Steve Beleck.
Olympiakos, 1-0 winners over Marseille in the Champions League on Wednesday, came crashing back down to earth with a 2-0 defeat at struggling Tripolis who won for only the second time in nine matches.
Rogerio gave Tripolis a 42nd-minute lead from the penalty spot after he picked himself up to slot home following a foul by Olympiakos goalkeeper Balazs Megyeri.
The Reds' Hungarian keeper was beaten again with 20 minutes left after he came rushing out of his goal only to be lobbed superbly by Tripolis' Argentine striker Emanuel Perrone.
Olympiakos coach Ernesto Valverde admitted his team's first defeat of the season had damaged their title hopes.
"The truth is after this loss, things are very difficult for us as far is the title is concerned," said the Spaniard, whose team face Arsenal at home in their final Champions League group match on December 6.
"It is hard to take a defeat like this coming after a great victory in Europe which has filled our supporters with optimism. Nevertheless we will continue to strive and fight for the championship."
