His younger brother, Marcus Giles, is a former Major League infielder who was most notable for playing with the Atlanta Braves organization.

By 1994, Giles had worked his way up to Triple-A, where he batted .313 for Charlotte making the International League All-Star team.

In 2002, Giles drew a career-high 135 walks, ranking him second in the National League behind San Francisco's Barry Bonds, who led with 198.

His .450 on-base percentage tied him for the second-best mark in the majors, he also ranked second in the league in slugging percentage with .622, sixth in home runs, second with 80 extra-base hits ranked second behind San Francisco's Jeff Kent, tied for second in the league with 13 outfield assists and also finished third in the NL with 24 intentional walks.

On August 26, 2003, he was traded to his hometown San Diego Padres for Jason Bay, Óliver Pérez, and minor leaguer Corey Stewart.

In 2007, joined by his brother Marcus, signed as a free agent to be the starting second baseman, Giles batted .271, but missed time with an injured knee.

In 2008, Giles, in the third and final guaranteed year of his contract with the Padres, vetoed a potential trade to Boston,[3] citing a desire to remain close to his family.

[1] In 2009, through July 1 Giles had the lowest batting average (.191), slugging percentage (.271), and OPS (.548) in the major leagues.

On February 7, 2010, Giles signed a minor league contract with the Los Angeles Dodgers and received an invitation to spring training.

A jury found that both Giles and his girlfriend, Cheri Olvera, committed acts of domestic violence against each other but that there were no damages.

As of August 22, 2018 the San Diego Padres have cut ties with Brian Giles and his brother Marcus, over domestic violence issues.