In 1991, at age 21, Kotzen joined glam metal band Poison, co-writing and performing on the album Native Tongue.

In 1999, Kotzen replaced Paul Gilbert as guitarist in the mainstream hard rock band Mr. Big, performing on their album Get Over It.

In 2001, while still in Mr. Big, Kotzen recorded and released another solo album called Slow, which contains a mix of bluesy rock for which a music video was filmed.

In 2005, Kotzen teamed up with three Japanese punk rockers to form the short-lived Forty Deuce-Project, which only lasted long enough to record and release one album.

Later in the same year, Kotzen collaborated with Funk Rock Fusion guitarist Steve Saluto on his album Rough Beat.

During the year 2006, Kotzen produced and released two solo studio albums, first Ai Senshi Z×R, an album on which he played several English sung rock covers of theme songs from the Japanese Gundam anime franchise, and only nine months later Into the Black, containing ten self-penned rock songs In 2007, Go Faster was released, which alternatively was named Return of the Mother Head's Family Reunion in Europe and Japan.

It includes the eight-minute-song "Fooled Again", and the soft pop ballad "Chase It", for which a music video clip was filmed in Venice.

Kotzen's wife, bassist/vocalist Julia Lage, added some background vocals and also appears in the music video for the song "In An Instant".

On the song "I'm All In" Kotzen shares the vocals with Doug Pinnick of King's X Only nine months later, on October 2, 2015, The Winery Dogs released their second album Hot Streak, followed by another world tour.

On January 25, 2018, Kotzen released a video for his new single called The Damned, a heavy blues rocker, via YouTube, which was filmed at Paramount Ranch in Agoura, California by director Vicente Cordero.

On June 11, 2019, another solo single titled Venom was published, in the style of The Winery Dogs, accompanied by a music video.

For the song "Devil's Hand", a video clip was filmed by the seaside, which was again directed by Vicente Cordero, and also includes scenes with Kotzen's wife, Julia Lage.

Another music video for the song "As You Are" was shot by Kotzen himself, dancing and playing in his kitchen wearing a pajama, while he was in quarantine with COVID-19.

In the second half of 2020, Kotzen began working on a project called Smith/Kotzen with Iron Maiden guitarist Adrian Smith.

Kotzen has described his style as a mix of rock, blues, heavy metal, jazz, fusion, and soul music.

As his main influences, he lists Jimi Hendrix, Stevie Ray Vaughan, Eddie Van Halen, Jason Becker (who produced his first album), Allan Holdsworth, and many other jazz and fusion players.

Both the amplifier head and the speaker cabinets were the only Cornford models generally supplied with Kotzen-spec black Tolex covering.