He won the 2004 Tony Award for Best Book of a musical for Avenue Q, written with composers Robert Lopez and Jeff Marx, which opened at Broadway's John Golden Theatre in 2003 and ran commercially in New York City for sixteen years.

Among dozens of international productions and two national tours, the musical ran for six years on London's West End, as produced by Cameron Mackintosh.

In 2015, Whitty premiered his original vision of Head Over Heels (musical) at the outdoor 1100-seat Allen Elizabethan Theatre at the Oregon Shakespeare Festival.

Whitty devised the jukebox musical as a hybrid of Sir Philip Sidney's The Countess of Pembroke's Arcadia and the back catalog of 80's pop stars The Go-Go's.

New York Times drama critic Charles Isherwood praised Whitty's book as "deliciously witty, bawdy and full of loopy appeal — and written mostly in skillfully wrought iambic pentameter yet.

[11][12] In 2018, Fox Searchlight Pictures released Can You Ever Forgive Me, with a screenplay by Whitty and Nicole Holofcener, adapted from a memoir by Lee Israel.

Whitty's plays include The Further Adventures of Hedda Gabler which was commissioned by and received its world premiere at South Coast Repertory in January, 2006; The Plank Project (a parody of documentary theater pieces like The Laramie Project); the multi-play cycle Balls; The Hiding Place, a romantic Manhattan comedy which received its New York debut at the Atlantic Theater Company; the dark comedy Suicide Weather.

Whitty is an occasional actor, having appeared in New York productions of plays by Amy Freed, including The Beard of Avon and Freedomland, as well as small roles in the films Garmento, Lisa Picard is Famous, and a cameo in Shortbus.