Karros was drafted by the Los Angeles Dodgers in the 6th round of the 1988 Major League Baseball Draft. He made his Major League debut as a pinch runner on September 1, 1991 against the Chicago Cubs. He made his first start, at first base, on September 4, 1991 against the St. Louis Cardinals, when he was 0 for 3 with 2 strikeouts. Karros recorded his first Major League hit as a pinch hitter in the bottom of the 12th inning against the Cincinnati Reds Milt Hill on September 16, 1991. The hit was a 2 RBI double to left field. In 14 appearances during the 1991 season, he only had the 1 hit in 14 at-bats.
In his first at-bat of the 1992 season, on April 9 against the San Diego Padres, Karros hit a 2 run home run 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 ( 5, matched by only Duke Snider and Gil Hodges ). Eric also remains the only player in Dodger history to hit two home runs in the same inning. 1999 was his best statistical year with the Dodgers, a batting average of .304 with 34 home runs and 112 runs batted in. His 270 home runs as a Dodger remains the third most in Dodgers 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 season. 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 of 2014 it was announced that Brennaman and Karros would continue to call FOX games together, however the pair had been reassigned to the No.3 booth.