The 29-year-old Russian, who had saved three match points to squeeze past French qualifier Thierry Ascione in the first round of his final tournament on Monday, fought bravely against the Argentine world number five.
Showing glimpses of his old form, Safin, who has not won a title since the 2005 Australian Open, challenged Del Porto by winning a tight second set.
Safin, who held the number one spot for several weeks in 2000-2001, was broken in the third game of the decisive set and his opponent then stayed in control.
The Russian, who won the Paris event three times, saved a match point at 5-3 down with a forehand winner but Del Potro then served for the match, sealing victory with an ace.
The gifted but erratic Russian, who also won the 2000 US Open, defeating Pete Sampras in a memorable final, was once regarded as one of the world's most spectacular players and will also be remembered for his rebellious spirit and dry humour.
Djokovic advances
Novak Djokovic survived a fightback by Argentine Juan Monaco to win 6-3, 7-5 and reach the third round of the Paris Masters.
Serb Djokovic, seeded third in the indoor event, controlled the first set but was then challenged by his unseeded opponent.
The 22-year-old world number three saved a set point with a volley at 5-2 down in that second set and recovered to seal victory when Monaco hit a forehand into the net on the first match point after an hour and 32 minutes.
Djokovic, who beat world number one Roger Federer in the Basel final on Sunday to win his fourth title this year, next faces German Tommy Haas or Frenchman Arnaud Clement.
Swede Robin Soderling, seeded ninth, kept alive his slim hopes of making the November 22-29 World Tour Finals in London by beating towering Croatian Ivo Karlovic 6-4, 7-6 to set up a third-round match against Russia's Nikolay Davydenko.
First look: Del Potro atop Empire State Building
Impossible is something for Marat Safin