Stuart McCall's side had their fair share of possession and half-chances in the third qualifying round clash but lasted just 13 minutes of their debut in the competition before conceding.
The manner of the goal would have been deeply frustrating for McCall as an inswinging free-kick from Lazaros Christodoulopoulos found its way inside Darren Randolph's far post as the home side failed to attack the delivery.
Motherwell quickly settled and kept possession well while creating several decent half-chances if not a killer opportunity.
But substitute Charis Mavrias broke away in the 76th minute to give Motherwell a mountain to climb to reach the play-offs when they travel to Athens next week.
McCall picked an attacking team with strikers Michael Higdon and Henrik Ojamaa both starting along with wingers Chris Humphrey and Jamie Murphy.
Visiting manager Jesauldo Ferraira expressed concern on the eve of the game that summer changes at his club could lead to a shock and Greece captain Giorgios Karagounis did not travel to Scotland amid a contract dispute.
But the visitors only had one summer signing in their line-up and Motherwell made a nervous start with a free-kick from Christodoulopoulos and a header from Jose Toche clearing the bar inside five minutes.
But the 9,035 Fir Park crowd were lifted by positive runs from Motherwell's wide players and Humphrey fired inches over from 25 yards following a short corner.
The dreaded away goal soon came though and it was bitterly reminiscent of the strike that killed off Motherwell's UEFA Cup tie against Nancy four years ago.
Centre-back Shaun Hutchinson, who started alongside debutant Simon Ramsden despite being restricted to 45 minutes of pre-season action by a groin injury, was penalised for a push on Ibrahim Sissoko near the left touchline.
Christodoulopoulos swung the free-kick in from about 40 yards and Jean-Alain Boumsong made an unchecked run across the box.
The former Rangers and Newcastle defender did not appear to get a touch as the ball flashed past his body but the run was enough to put off Randolph and the ball curled inside the Irishman's far post.
The goal slightly deflated a vibrant atmosphere although Motherwell produced a decent initial response, keeping possession for long spells against a Greek side now content to sit in.
Humphrey got on the end of Murphy's back-post cross but could not turn it on target and Keith Lasley fired over with his left foot after Murphy threaded the ball into his path.
Ojamaa had a sight of goal but his hesitation allowed Jose Manuel Velazquez to take the sting out of his shot.
Higdon then got a header on target from Murphy's cross but it was straight at Orestis Karnezis.
Well were guilty of some slack passing in the final stages of the half and the Greeks had several efforts from long range with the pick a 25-yard strike from Jose Carlos Zeca that Randolph pushed over.
Christodoulopoulos curled just wide from 25 yards 30 seconds after the restart but at the other end Karnezis was soon tested by Tom Hateley's 30-yard free-kick, taking no chances on the wet surface by pushing the ball to safety.
The goalkeeper almost spilled Nicky Law's shot from a similar distance into his net and Higdon won Hateley's cross but again directed it at Karnezis.
Loukas Vyntra found the side net after a one-two with Ivorian Sissoko, who caused Motherwell problems all night with his movement.
But Motherwell responded again and only a brilliant sliding block from Boumsong stopped Law converting after Ojamaa had cut open the away defence.
Motherwell briefly had their visitors on the ropes and Ojamaa then wasted a good chance on the break when he failed to play in Murphy as he raced clear on the left.
Panathinaikos showed them how to do it moments later. Ojamaa lost the ball on the edge of the Greek box after a Motherwell free-kick and the visitors cleared the ball to Sissoko, who played a perfect through ball for right winger Mavrias and he fired the ball through Randolph's legs.
Motherwell continued to push forward but could not carve out a late chance that would have given them even a glimmer of hope of avoiding the drop into the Europa League play-offs.
More clever play from Sissoko almost finished Well off but sub Bruno Fornaroli blazed over.