His principal works include an opera The Children of Rosenthal (Vladimir Sorokin, libretto); ballets Lost Illusions and Opera, a chamber opera Poor Liza after Nikolay Karamzin; Gift, a cantata on poems by Gavriil Derzhavin; Dichterliebe und -leben, a vocal cycle on poems by Daniil Kharms and Nikolay Oleynikov; The Leaden Echo for voice(s) and instruments on the poem by Gerard Manley Hopkins; The Rite of Winter 1949, a symphony for choir, soloists and orchestra; Songs of Bukovina for piano.

His principal compositions include: The Children of Rosenthal (an opera in two acts; libretto, Vladimir Sorokin), commissioned by the Bolshoi Theatre; Poor Liza (a chamber opera in one act; libretto, Leonid Desyatnikov, after the novel by Nikolai Karamzin); Gift (a cantata based on the verses of Gavrila Derzhavin); The Leaden Echo (a work for voice(s) and instruments based on the poem by Gerard Manley Hopkins); and The Rite of Winter 1949 (a symphony for chorus, soloists and orchestra).

Desyatnikov has been collaborating with Gidon Kremer since 1996 as a composer (Wie der Alte Leiermann...; the chamber version of Sketches to Sunset; Russian Seasons) as well as arranging the works of Astor Piazzolla, including the tango-operita María de Buenos Aires and the tango suite Cuatro estaciones porteñas.

Desyatnikov wrote the scores for the films Sunset (1990), Lost in Siberia (1991), Hammer and Sickle (1994), Moscow Nights (Katya Izmailova) (1994), Giselle’s Mania (1995), Prisoner of the Mountains (1996), All That Is Tender (1996), Moscow (2000), His Wife’s Diary (2000) and The Target (2010),[1] "Trompe-loeil" for piano four hands, Aldeburgh (2023, June), "Reflections on the Folk Song" for 19 strings and viola obbligata, Stockholm (2024, August), "Saint Petersburg, Florida", barcarola for two pianos, Padova (2024, September).

Desyatnikov is the author of four operas, the symphony The Rite of Winter 1949, vocal cycles to the poems of Rilke and the OBERIU poets, and several instrumental transcriptions of themes by Ástor Piazzolla.