Lewis was drafted in the second round, and was sent to the short season-A Salem-Keizer Volcanoes. While there, earned Northwest League All-Star honors, leading the league with a.322 batting average, while finishing 5th for both hits and on-base percentage. Lewis also was named co-Player of Month for July, along with Dan Ortmeier and Greg Bruso. Lewis spent all of 2003 with the Hagerstown Suns, where he finished the season second in the Giants organization with 30 stolen bases. He also led the team with 61 runs scored, while ranking 3rd in games and doubles. Lewis finished the season with a.250 batting average, but as a result of leading the team in walks with 68, wound up with a.361 on-base percentage. Lewis starred on the Norwich Navigators in Norwich, Connecticut, where it was customary for fans to shout his name while he was at bat, on deck, running in from the field or anywhere else in view. Lewis would choose the loudest fans to join him in Fred Lewis' Pancake Breakfasts.
Major leagues
San Francisco Giants
Lewis was a September call-up in 2006, making his debut on September 1 at Wrigley Field against the Chicago Cubs; he had a base hit in each of his first three at bats. Lewis finished the year 5-11 with 2 RBI. Lewis made his first appearance on a Major League 25-man roster on May 6, 2007, and hit for the cycle on May 13, Mother's Day, in only his 16th game in the majors at Colorado. Lewis doubled leading off the game, then hit a three-run opposite-field home run in the fourth inning, followed by an RBI triple in the fifth and a single leading off the seventh inning. Lewis' cycle was the 22nd in Giants franchise history. Lewis is one of only a handful of Major League baseball players to hit his first homer as part of a cycle. On June 1, Lewis hit his first MLB grand slam against the Philadelphia Phillies. About a month later, on July 4, Lewis hit another grand slam against the Cincinnati Reds, becoming the first player in San Francisco Giants history to hit two grand slams in his rookie season. On April 26, 2008, Lewis hit the 46th Splash Hit at AT&T Park. Lewis led the majors in steals of home in 2008 with 2, but was also caught twice while attempting to steal home.
On April 16, 2010, Lewis was traded to the Toronto Blue Jays. Lewis had a somewhat successful stay with Toronto, batting first in the batting order on a regular basis with a.276 batting average. On December 3, 2010, the Blue Jays declined to tender a contract to Lewis prior to the non-tender deadline, thereby making him a free agent. On January 10, 2011, it was announced that he signed with the Cincinnati Reds to a 1-year $900,000 deal. He elected free agency on October 27.
Cleveland Indians
Lewis signed a minor league contract with the Cleveland Indians on January 19, 2012, which included an invitation to the Indians' spring training camp. On April 2, Lewis was released by the Indians.
On April 25, 2012, Lewis signed a minor league contract with the New York Mets. On September 3, 2012, the Mets selected the contract of Lewis as rosters expanded in September. He posted a.150/.320/.150 in 25 plate appearances over 18 games and was then outrighted off the 40-man roster on October 16, 2012, and opted to become a free agent.
On November 9, 2012, Lewis signed a one-year, $400,000 deal with a club option for 2014 with the Hiroshima Toyo Carp of Nippon Professional Baseball. The deal included a $150,000 signing bonus.
