The 49ers held the Chargers to two first-half field goals while closing out their exhibition record at 3-1.
Kaepernick, who emerged as San Francisco's starter last season, completed 3-of-4 for 64 yards and hit Quinton Patton with a 43-yard touchdown pass on the 49ers' first possession.
Colt McCoy and B.J. Daniels also threw for San Francisco touchdowns -- McCoy hitting Anthony Dixon with a 5-yarder midway through the second quarter and Daniels finding Chuck Jacobs from 14 yards out in the final minutes.
The 49ers also scored in the second half when Cam Johnson fell on a blocked punt in the end zone.
The Chargers went 1-3 during preseason.
San Diego will be at home against Houston to begin the regular season in the second of the two Monday night games on the opening week calendar. San Francisco will host Green Bay on Sept. 8 in a rematch of one of last season's NFC divisional round playoff games, won by the 49ers 45-31.