Forsythe, who has made 69 starts this season at second base, was a late scratch before the Padres' game Thursday against the Dodgers.
"It wasn't one event. ... It was something he felt coming on," said Padres manager Bud Black. "I think that it manifested itself in the batting cage early on and he felt some discomfort taking ground balls."
Forsythe was replaced in the lineup Thursday by Andy Parrino, who got the start at second base Friday in the first game of a three-game series against the Giants at Petco Park.
This isn't the same knee that Forsythe had surgery on last fall, when he had a procedure done to repair his left meniscus.
Forsythe has impressed this season after missing the first 54 games of the season after breaking a bone in his left foot in Spring Training.
He has a slash line of .282/.352/.396 in 298 at-bats with five home runs and 24 RBIs this season and has been the starting second baseman for most of the second half but has also started games at shortstop and third base.