In 1984 he formed Bruce Hornsby and the Range, who were signed to RCA Records in 1985. Besides Hornsby, Range members were David Mansfield (guitar, mandolin, violin), George Marinelli (guitars and backing vocals), Joe Puerta (bass guitar and backing vocals), and John Molo (drums).

Hornsby's recording career started with the biggest hit he would ever have, entitled 'The Way It Is'. With a propulsive yet contemplative piano riff and the refrain, That's just the way it is, some things will never change, the song was both catchy and reflective of the American Civil Rights movement, and it topped the American music charts in 1986.

With the success of the single worldwide, the album The Way It Is went multi-platinum and produced another top five hit with 'Mandolin Rain'. Hornsby and the Range would go on to win the Grammy Award for Best New Artist in 1987.

The wave of fame continued to roll with Hornsby and the Range's second album, Scenes From The Southside (on which Peter Harris replaced Mansfield). Released in 1988, it featured such hits as 'Look Out Any Window' and 'The Valley Road'. The song 'Jacob's Ladder' was featured as well, having originally been written by Hornsby for musician friend Huey Lewis. Lewis' version became a number one hit from his album Fore!.
In 1988, Hornsby first appeared on stage with The Grateful Dead, lending some assistance to that group's somewhat unstable keyboards position. This collaboration would continue on an irregular basis until the Dead ended in 1995; in all he made over 100 appearances with them. In 1989 Hornsby co-wrote and played piano on Don Henley's big hit 'The End of the Innocence'. In 1991 Hornsby played piano on Bonnie Raitt's popular hit 'I Can't Make You Love Me'.

Hornsby would go on to release his first solo album, Harbor Lights, in 1993. This record showcased Hornsby in a more jazz-oriented setting and featured an all-star lineup, including Pat Metheny, Branford Marsalis, Jerry Garcia, Phil Collins, and Raitt.

Harbor Lights was well-received by critics and fans, but Hornsby acknowledged that his days of popular commercial success were behind him, saying in interviews that it had been an accident that his McCoy Tyner-influenced piano work ever found itself in the middle of a hit record in the first place.

In 1995, Hot House was released. The jazz feelings that peppered the previous album would be expanded on here, giving the album a constant uptempo party sound.

Hornsby next worked with several Grateful Dead reformation projects, released a live album in 2000 entitled Here Come The Noise Makers, and did extensive touring.

However, in 2004, after 19 successful years on RCA Records, Hornsby returned to a more acoustic, piano-driven sound on his Columbia Records debut Halcyon Days. Guests included Sting, Elton John, and Eric Clapton.

In July 2006, Hornsby released a box set titled Intersections {1986-2006} to celebrate two decades of his music.