The north London club took an early lead through the Togo striker before being pegged back by Zeca's second half strike, but rallied to claim all three points at White Hart Lane.
Spurs had only needed to draw to guarantee their place in the next round, but strikes from Emmanuel Adebayor and Jermain Defoe, plus an Orestis Karnezis own goal ensured they proceeded to the last 32 with a win.
Adebayor had given the home side the lead midway through the first half before Zeca equalized after the break, but Spurs, still unbeaten in Europe this season, rallied to claim three points.
Andre Villas-Boas made four changes to the team that beat Fulham 3-0 at the weekend, with Brad Friedel, Kyle Walker, Tom Carroll and Adebayor all selected in a 4-4-2 formation.
The away side retained seven of the starting XI that drew with Spurs in Athens. The goal scorer that night, Toche, lined up in attack, though former Arsenal winger Quincy Owusu-Abeyie missed out through injury.
Tottenham exerted a degree of control from the start, with Carroll, Steven Caulker and Jan Vertonghen seeing a lot of the ball, but the home side struggled initially to break down an organized and austere Greek defense.
It was Panathinaikos’ Spanish forward Toche who came closest to opening the scoring, flicking Giourkas Seitaridis’ free kick into the grateful arms of Friedel from 6-yards, though he should have been flagged for offside.
But Spurs made the breakthrough when Clint Dempsey threaded a pass behind Kostas Triantafyllopoulos for Adebayor to collect. The Togolese forward shifted the ball onto his right foot before caressing it past Karnezis.
Tottenham could have doubled the lead before the break when Adebayor latched onto Carroll’s through ball, but Triantafyllopoulos slid in to block his shot. From the resulting corner, Vertonghen headed just wide.
Dempsey was enjoying himself in the hole, and after the break he played Jermain Defoe through on goal to rattle the post from an acute angle.
But for all Spurs’ superiority, it was the Greek side which would strike next. Nikos Spyropoulos played a deep cross to the back post which Zeca, having lost Kyle Naughton, headed back across goal and past a hapless Friedel.
The goal invigorated Panathinaikos and rattled the home side. Spurs’ control evaporated and was replaced by a nervousness typified by Naughton’s hurried clearance that landed at the feet of Toche, who rolled the ball wide from close range.
But Spurs re-took the lead against the run of play after Sandro’s lung-busting run produced a free kick on the edge of the area. Dempsey rose highest to meet Kyle Walker’s delivery, thumping a header against the bar which ricocheted off Karnezis’ back and trickled over the line.
The rout was completed after Aaron Lennon embarked on a mazy run before reversing the ball for Defoe to calmly dink over the onrushing Karnezis in sublime style.
Elsewhere in Group J, Lazio hammered Maribor 4-1, booking its place in the knockout stages as the group winner, so Spurs were forced to settle for second place.