The musical, directed by Michael Mayer, underwent several workshops in New York in 1999. Included in the workshops casts were Kristin Chenoweth, Marc Kudisch, and Beatrice Arthur.
It then played out-of-town tryouts at the La Jolla Playhouse at University of California, San Diego in October 2000 through December 2000. Despite nurturing the role through the workshop process, Kristin Chenoweth did not continue with the role of Millie in order to film her own sitcom. She was replaced by Erin Dilly, but prior to public previews, Sutton Foster was chosen from the chorus to assume the title role, a move that propelled her to stardom.
The musical premiered on Broadway at the Marquis Theatre on April 18, 2002 and closed on June 20, 2004 after 903 performances and 32 previews. Directed by Michael Mayer and choreographed by Rob Ashford, orchestration was by Doug Besterman and the late Ralph Burns, scenic design was by David Gallo, costume design was by Martin Pakledinaz, and lighting design was by Donald Holder. The original cast included Sutton Foster as Millie, Marc Kudisch as Trevor, Angela Christian as Miss Dorothy, Gavin Creel as Jimmy, Harriet Sansom Harris as Mrs. Meers, Sheryl Lee Ralph as Muzzy Van Hossmere, Ken Leung as Ching Ho, Francis Jue as Bun Foo, and Anne L. Nathan as Miss Flannery.
Replacements later in the run included Susan Egan as Millie, Leslie Uggams as Muzzy, Delta Burke and Dixie Carter as Mrs. Meers, Christian Borle as Jimmy, Christopher Sieber as Trevor Graydon, and Liz McCartney as Miss Flannery. At the April 2, 2003 performance, Meredith Vieira appeared in three minor roles for a segment later broadcast on her daytime talk show The View.
The original Broadway production won six Tony Awards and five Drama Desk Awards, including the win for Best Musical at both award ceremonies.
In 2003, the original creative team reunited to stage the show in London's West End at the Shaftesbury Theatre. It began previews on October 11 and opened on October 21. Well-known UK TV personality Amanda Holden starred in the title role, with Maureen Lipman and Marti Webb alternating as Mrs. Meers and Sheila Ferguson as Muzzy Van Hossmere. When Webb subsequently left the production to join Tell Me on a Sunday, Mrs. Meers was played by Anita Dobson, and when Holden was forced to take time off due to illness, her understudy Donna Steele took over the role to great acclaim. Despite positive reviews and booking periods extended to January 2005, Thoroughly Modern Millie failed to catch the UK public's attention and closed on June 26, 2004.
A UK tour beginning in March 2005 fared much better and successfully toured many of the country's major theatres until November, when it closed as planned in Nottingham. The tour starred Steele as Millie, Lesley Joseph as Mrs. Meers, and Grace Kennedy as Muzzy Van Hossmere.