The theatre was built as one of a pair with the Aldwych Theatre on either side of The Waldorf Hilton, London, both being designed by W. G. R. Sprague. The theatre was opened by The Shubert Organization as the Waldorf Theatre on 22 May 1905, and was renamed the Strand Theatre, in 1909. It was again renamed as the Whitney Theatre in 1911, before again becoming the Strand Theatre in 1913. In 2005, the theatre was renamed by its owners (Delfont Mackintosh Theatres) the Novello Theatre in honour of Ivor Novello, who lived in a flat above the theatre from 1913 to 1951.
In 2006, the theatre played host to the London première of the Broadway musical Footloose, starring Cheryl Baker. Ending on 11 November, Footloose made way for the Royal Shakespeare Company's return season for 2006–7, following which the Broadway musical The Drowsy Chaperone made its European première on 6 June 2007. The London production starred Elaine Paige, Bob Martin, Summer Strallen and John Partridge. The London production closed after a run of only two months on 4 August 2007 after failing to attract audiences, despite positive notices.
It was announced on 10 July 2007, just three days after the announcement of Drowsy's premature closure that the theatre would be the home of a new musical version of the MGM motion picture Desperately Seeking Susan with music by Blondie and Deborah Harry, directed by Angus Jackson, and starring Emma Williams and Kelly Price. The musical previewed on 16 October 2007 (originally 12 October 2007), receiving its world première on 15 November 2007. However, just two weeks after its opening, following a critical mauling, the show announced its final performance for 15 December 2007, having played just four weeks of previews and four weeks of open run, losing over £3.5 million.
A quick replacement came in the form of the cross-West End transfer of Shadowlands from the Wyndham's Theatre, commencing 21 December 2007 for a 12-week run to 25 February 2008. Producer Phil McIntyre opened ZooNation's adaptation of the musical Into the Woods, entitled Into the Hoods, on 26 March 2008.
The longest running show in modern times is Mamma Mia!, which premiered on 6 April 1999 at the Prince Edward Theatre. It transferred to the Prince of Wales Theatre 9 June 2004 – 1 September 2012. It then transferred to the Novello Theatre on 6 September 2012 where it is still running in 2026.
In 2020, following the nationwide lockdown due to the COVID-19 pandemic, Delfont Mackintosh Theatres Ltd laid off most of the theatre's staff and in August 2020 they were facing redundancy.