The World Player of the Year picked up where he left off in last year's edition of Europe's elite club competition, when he was the top scorer, pulling Barca level after the Greek champions had taken a shock 20th-minute lead and running the visiting defence ragged.
GEAR:2010/11 Champions League kits. Get your new shirt here with our online retailer Kitbag
His second goal came after a brilliant passing move that typified Barca's electric playing style and he created their fifth of the night for defender Daniel Alves with a sublime chip that left the hapless Panathinaikos players rooted to the spot.
David Villa and Pedro completed the rout, Pedro's goal coming after Messi's shot from an acute angle bounced back off the far post, ricocheted off the other upright and fell perfectly for the Spain forward to tap across the line.
The 23-year-old Argentine's performance, showcasing the full range of his talent, recalled his four-goal destruction of Arsenal at the same Nou Camp arena last season.
"He is the best player in the world by some distance from the rest," coach Pep Guardiola said at a news conference.
"It hurts him to miss and he has this amateur spirit of always wanting to play.
"We limit ourselves to deploying him where he feels most comfortable. He is ambitious, he likes training very much and he's a great lad."
Sidney Govou sprinted on to Djibril Cisse's clever flick and fired clinically past Victor Valdes.
An athletic leap from Sergio Busquets created Barca's second for Villa just after the half hour. The midfielder rose to nod a Xavi corner into his Spain team mate's path and Villa swept the ball home with aplomb.
After Pedro's effort made it 4-1 with just over 10 minutes of regular time left, Alves raced clear and sent a looping header over Tzorvas from Messi's chip in added time.
"We are very pleased because it's always difficult playing your first match of the competition," Pedro said in an interview with Spanish television.
"We knew we
