In his first at-bat of the 1992 season, on April 9 against the San Diego Padres, Karros hit a two-run shot to deep left field off of Craig Lefferts for his first career home run. He became a full-time starter for the Dodgers that season, appearing in 149 games and hitting 20 home runs while driving in 88 runs. He was named the 1992 National LeagueRookie of the Year. Karros put up consistent numbers throughout his career with the Dodgers, with a batting average just under .270 and an average of almost 25 home runs a year. No Dodger in the organization's history compiled more 30 home run 100 RBI seasons than Karros (five, matched only by Duke Snider and Gil Hodges). Karros also remains the only player in Dodger history to hit two homers in the same inning. 1999 was his best statistical year with the Dodgers, when he hit .304 with 34 home runs and 112 RBI. His career 270 home runs as a Dodger remains the third most in the team's history.
On December 2, 2002, he was traded along with Mark Grudzielanek to the Chicago Cubs in exchange for Todd Hundley and Chad Hermansen. After playing the 2003 season with the Cubs he was granted free agency from the team at the end of the year. In 114 games with the Cubs, he hit .286 with 12 home runs and 40 RBI.
He then signed with the Oakland Athletics before the start of the 2004 season. Karros’ final MLB game was on July 21, 2004, and he was released by the Athletics on August 3, 2004. He only appeared in 40 games with the team, hitting .194 with 2 home runs and 11 RBI.
Karros was hired to call regional games for Fox Saturday Baseball in 2007. He was promoted to the No.2 team in 2011 primarily calling games with Thom Brennaman. In March 2014 it was announced that Brennaman and Karros would continue to call FOX games together, and the pair called the first regular season game ever on Fox Sports 1.