Mehldau studied music at The New School, and toured and recorded while still a student. He was a member of saxophonist Joshua Redman's Quartet with bassist Christian McBride and drummer Brian Blade in the mid-1990s, and has led his own trio since the early 1990s. His first long-term trio featured bassist Larry Grenadier and drummer Jorge Rossy; in 2005 Jeff Ballard replaced Rossy. These bands have released a dozen albums under the pianist's name.
Since the early 2000s Mehldau has experimented with other musical formats in addition to trio and solo piano. Largo, released in 2002, contains electronics and input from rock and classical musicians; later examples include touring and recording with guitarist Pat Metheny, writing and playing song cycles for classical singers Renée Fleming and Anne Sofie von Otter, composing orchestral pieces for 2009's Highway Rider, and playing electronic keyboard instruments in a duo with drummer Mark Guiliana.
Aspects of pop, rock, and classical music, including German Romanticism, have been absorbed into Mehldau's writing and playing. Through his use of some traditional elements of jazz without being restricted by them, simultaneous playing of different melodies in separate hands, and incorporation of pop and rock pieces, Mehldau has influenced musicians in and beyond jazz in their approaches to writing, playing, and choice of repertoire.