Gales picked up the guitar at age four. His older siblings, Eugene and Manuel (Little Jimmy King), taught him songs and licks when he was young, in the style of Jimi Hendrix, Albert King, B.B. King and others. In 1985, the young Gales began to play at blues competitions with his brother Eugene backing him on bass. Although Gales plays a right-handed guitar "upside-down" (with the bass E string on the bottom), he is not naturally left-handed; he was taught by his brother, who is left-handed, and never second-guessed the untraditional technique.
In late 1990, Eric and Eugene Gales signed with Elektra Records, and together with the drummer Hubert Crawford released The Eric Gales Band (1991) and Picture of a Thousand Faces (1993). Guitar World magazine's Reader's Poll named Eric the "Best New Talent", in 1991. During this time he had two rock radio hits, "Sign of the Storm" (number 9, U.S. Mainstream Rock) and "Paralyzed" (number 31, U.S. Mainstream Rock) and had spots on television programs such as The Arsenio Hall Show.
In 1994, Gales performed with Carlos Santana at Woodstock '94. In 1995, Gales teamed up with both of his brothers to record an album, Left Hand Brand (released in 1996), as the Gales Brothers. In 2001 Gales released his album That's What I Am on MCA Records.
Gales has released the albums Crystal Vision, The Psychedelic Underground, The Story of My Life and Layin' Down the Blues on the Shrapnel Records label. Relentless (2010) was followed by Transformation (2011) and Live (2012).
Gales has two daughters, Jasmine Gales (born 1992) and stepdaughter LaAsia Chandler (born 1996) and is married to LaDonna Gales, from Greensboro, North Carolina.
In 2004, he contributed a cover of "May This Be Love" to the album Power of Soul: A Tribute to Jimi Hendrix. In 2008, he and other guitarists participated in the touring tribute to Jimi Hendrix, Experience Hendrix. The touring group of musicians included Billy Cox, Eric Johnson, Chris Layton, Doyle Bramhall II, Brad Whitford and Mitch Mitchell (it was the last tour that Mitchell played on).
In the winter of 2010, Gales returned to the touring circuit in Europe with TM Stevens on bass guitar and Keith LeBlanc on drums. The tour was billed as VooDoo Chile and featured works of Jimi Hendrix as well as original material from both Gales and Stevens.
In February 2013, Magna Carta Records released the album Pinnick Gales Pridgen, produced by Mike Varney and featuring Gales on guitar and vocals, Doug Pinnick on bass and vocals, and Thomas Pridgen on drums. The 13-track album featured one cover song, "Sunshine of Your Love", originally by Cream, one short instrumental based on Ludwig van Beethoven's "Für Elise", and the remaining songs written by some combination of Pinnick, Gales, Pridgen and Varney. The follow-up album, PGP2, was released in July 2014.
In 2017, Gales released his fifteenth studio effort, Middle of the Road, featuring numerous artists, including Gary Clark Jr., Lauryn Hill and others, as well as his own brother and mother. The album became his first to chart on Billboard's Top Blues Album chart, peaking at No. 4, and Gales’ next album, The Bookends, topped the chart at No. 1. On May 9, 2019, he won the Blues Music Award for 'Blues Rock Artist of the Year'. In his acceptance speech, he said he was celebrating three years of sobriety. In May 2020, Gales won his second consecutive Blues Music Award as the 'Blues Rock Artist of the Year