He was Oscar-nominated for The Queen (2006), The Curious Case of Benjamin Button (2008), Fantastic Mr. Fox (2009), The King's Speech (2010), Argo (2012), Philomena (2013), The Imitation Game (2014), Isle of Dogs (2018), and Little Women (2019).

Desplat has composed scores for a wide range of films, including low-budget independent productions and large-scale blockbusters, such as The Golden Compass (2007), The Twilight Saga: New Moon (2009), Harry Potter and the Deathly Hallows – Part 1 (2010) & Part 2 (2011), Moonrise Kingdom (2012), Zero Dark Thirty (2012), Unbroken (2014), The French Dispatch (2021), and Guillermo del Toro's Pinocchio (2022).

He began collecting Bernard Herrmann's Hitchcock soundtracks as a teen and eventually decided to pursue a career as a film composer after hearing John Williams's Star Wars score in 1977.

His big Hollywood break came in 2003 with the soundtrack for the film Girl with a Pearl Earring, a drama set in 17th-century Delft exploring a fictional muse of Vermeer.

[7][11] Desplat has composed extensively for French cinema, Hollywood, and incidental music for over 100 films, including Lapse of Memory (1992), Family Express (1992), Regarde Les Hommes Tomber (1994), Les Péchés Mortels (1995), César-nominated Un Héros Très Discret (1996), Une Minute de Silence (1998), Sweet Revenge (1998), Le Château des Singes (1999), Reines d'un Jour (2001), the César-nominated Sur mes lèvres (2002), Rire et Châtiment (2003), Syriana (2005), the César-winner The Beat That My Heart Skipped (2005), The Queen (2006), Fantastic Mr. Fox (2009), Harry Potter and the Deathly Hallows – Part 1 (2010), The Ghost Writer (2010), Daniel Auteuil's remake of La Fille du Puisatier (2011), Harry Potter and the Deathly Hallows – Part 2 (2011) and The Grand Budapest Hotel (2014).

Desplat has composed individual songs that have been sung in films by such artists as Akhenaton, Kate Beckinsale, Charlotte Gainsbourg, Valérie Lemercier, Miosotis and Catherine Ringer.

Prior to these break-out works, he contributed scores for The Luzhin Defence, Girl with a Pearl Earring, Syriana, Birth, Hostage, Casanova and The Nest.

Desplat has composed music for Largo Winch, based on the Belgian comic; Afterwards a French-Canadian psychological thriller film directed by Gilles Bourdos in English; Anne Fontaine's Coco avant Chanel, based on the life of designer Coco Chanel; Robert Guédiguian's L'Armée du Crime; Cheri, reuniting him with director Stephen Frears, whom he collaborated with on The Queen; Un Prophète reuniting with director Jacques Audiard; Julie & Julia[12] directed by Nora Ephron; Fantastic Mr. Fox, directed by Wes Anderson and based on the novel by Roald Dahl; New Moon, directed by Chris Weitz; Roman Polanski's Ghost Writer; Tamara Drewe; The Special Relationship; and The King's Speech which earned Desplat his fourth Oscar nomination.

Desplat started 2012 with Extremely Loud and Incredibly Close, the Florent Emilio Siri-directed biopic Cloclo, and DreamWorks Animation's Rise of the Guardians.

In June 2013, Desplat's first Concerto for Flute & Orchestra premiered in France with flautist Jean Ferrandis and the Orchestre National des Pays de la Loire conducted by John Axelrod.

[19] His score for The Imitation Game was also nominated, and his win therefore marked the first time a composer had won against another of their own scores since John Williams won for Star Wars (beating Close Encounters of the Third Kind) in 1978, and only the seventh time overall (Alfred Newman, Bernard Herrmann, Max Steiner, Miklos Rozsa and Johnny Green are the only other composers to achieve this).