It was Wozniak's second defeat at Roland Garros by a world No. 1 after going out a year ago to then-top player Caroline Wozniacki.
"I've got to bring my game up a notch at the key moments," said Wozniak, who marked a personal anniversary in Paris.
"I'm happy because it's exactly a year since I returned from my second forearm tendinitis injury. I'm happy because I've played a lot of top players this year and my level has gone up."
Wozniak, from Blainville, Que., was unable to stop the Azarenka's momentum once the Belarussian found her winning rhythm.
The pair last played in 2006 in the final of an entry-level WTA event, with Wozniak retiring injured in that match.
"She used to hit hard in the juniors so I expected heavy hitting today," said Wozniak. "She plays differently than the other top players because she hits hard but also really close to the lines — she made me stretch a lot."
Wozniak opened with a first-round win over fellow Canadian and qualifier Heidi El Tabakh and then beat China's No. 34 Zheng Jie. But the 24-year-old was unable to produce the upset against Azarenka.
Wozniak's best showing at Roland Garros remains the fourth round three years ago. She now stands 9-10 this season and 10-6 at the French Open.
She ended with 21 winners and 20 unforced errors but converted on only two of seven break chances in just over one hour 20 minutes against Azarenka.
Wozniak got off to a promising start as she and Azarenka traded immediately breaks, with the top seed's serve under threat from four double-faults in her first few times on serve. She tossed her racquet at 4-4 after an error.
Wozniak saved break points in the fifth and seventh games before losing her serve in the ninth on a forehand to the net. Azarenka served out the set in the next game after 46 minutes.
"I missed a few forehands and it changed the momentum of the match," said Wozniak.
The second set began like the first, with the women trading breaks before Azaranka broke for 4-3 and carried that momentum through to victory on a first match point as Wozniak returned long.
Wozniak will play doubles on Saturday with Simona Halep of Romania and will probably go home to Montreal after Paris to end a long trip and start preparations for Wimbledon.