Jesualdo Ferreiria's Panathinaikos, unbeaten this season, produced a dominant display in the hostile atmosphere of PAOK's Toumba stadium, taking the lead through Cleyton's 25-yard free-kick just after the half hour.
Ghana forward Quincy drilled in a second in the 56th minute after great work down the right by Kostas Katsouranis before Sebastian Leto grabbed his eighth goal of the season with a low free-kick.
Vierinha netted a consolation for a disappointing PAOK from the penalty spot five minutes from time.
The Greens overtook big rivals Olympiakos, who surrendered a two-goal lead on Saturday to draw 2-2 against OFI, and moved two points clear of the Reds after collecting 16 points from six matches.
The result ended a 17-match winning streak on home soil for the champions.
"We have to put this game in the past and focus on the Champions League match against Dortmund," said Olympiakos coach Ernesto Valverde whose team travel to Germany for their fourth Group F match needing a positive result to keep their qualification hopes alive.
"We thought the game was won at 2-0 and that was a mistake. We conceded two sloppy goals from set-pieces and we have to work on our concentration," Valverde added.
Atromitos are level on 16 points with the Greens - but have an inferior goal difference - after their remarkable form continued with a 2-1 home win over Panionios.
AEK Athens returned to winning ways with a comfortable 3-0 home win over struggling Aris Salonika at the Olympic Stadium which lifted the Yellows up to fourth with 13 points from seven games.
