Jankovic, who won three straight titles heading into the tournament, said she was tired from her recent schedule.
"I didn't have any gas in the tank,'' she said. "I am not a machine. Flavia took advantage, she was the better one today.''
Jankovic fell to the ground at 6-5 of the first set and appeared to hurt her left wrist. Still, she broke Pennetta when the Italian double-faulted soon after.
She again went down while getting broken in the third game of the second set, and she soon called for a trainer to treat her bleeding right knee.
"I feel like I have been in the war, when I come off the court with bruises and cuts,'' Jankovic said.
The deciding set went with serve until Pennetta hit a backhand winner to lead 5-3. She had two match points in the next game and took the first of them with an ace.
Jankovic had been 5-0 against the 17th-ranked Pennetta, including a straight-set win in Moscow last week after the Italian had knocked out Venus Williams.
Pennetta said she tried to take more risks and challenge the top-ranked player.
"Last week I didn't have a lot of luck and today I was more aggressive,'' she said.
Jankovic, who has never made it past the second round at the Zurich Open, took over the No. 1 ranking this month after consecutive wins in Beijing, Stuttgart, Germany, and Moscow.
Her final tournament of the season will be the Nov. 4-9 WTA Tour championship in Doha, Qatar.
Also, 18th-ranked Victoria Azarenka of Belarus routed Monica Niculescu of Romania 6-0, 6-0. Niculescu, who upset seventh-seeded Anna Chakvetadze in the first round, failed to convert any of her six break-point chances.
In a match between two qualifiers, 18-year-old Petra Kvitova of the Czech Republic beat Sofia Arvidsson of Sweden 6-2, 6-1.
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