The reigning NFC West champions are hoping the 35-year-old Moss can fill a big void in coach Jim Harbaugh's version of the West Coast offense.
Moss is expected to come off the bench Friday, according to the San Francisco Chronicle. Michael Crabtree and Ted Ginn Jr. will start.
Moss, whose reputation has taken a hit for his sometimes questionable work ethic, signed a one-year contract with the 49ers in March. He last played for New England, Minnesota and Tennessee during a rocky 2010 season.
Moss said he initially retired for "personal reasons outside of football" and considered making a comeback late in the 2011 season before ultimately deciding to give his body more time to heal. He suffered a shoulder injury in 2010 while with New England.
Moss' best season came for the Patriots in 2007, when he caught 98 passes for 1,493 yards and an NFL single-season record 23 touchdowns in helping New England to a 16-0 regular-season record. He has 954 catches for 14,858 yards and 153 TDs in his career, which started with the Vikings in 1998.
Information from The Associated Press was used in this report.