Since 2006, he has released nine studio albums, many of which are collaborative, including 2017's Planetarium with Sufjan Stevens, Bryce Dessner & James McAlister.

[6] He graduated from the former in 2003 with a Bachelor of Arts in English and received a Master's degree in music in 2004 from Juilliard, where he studied composition with John Corigliano and Christopher Rouse.

[9] As a first-year master's student at Juilliard at age 22, Muhly began working for Philip Glass as an archivist, and later an editor, conductor, and keyboardist, for eight years.

Gilmore International Keyboard Festival commissioned "Drones & Piano" for pianist Bruce Brubaker, which premiered in May 2010.

[20][21][22] According to a 2008 New York Times article, the opera is based on a late-1990s British case involving a 14-year-old boy taking on the online identity of women to try to get someone to kill him, without success.

[23] However, in a 2008 interview with The Advocate, Muhly stated that the opera is based on the true story of an online friendship between two male teenagers, one of whom stabs the other.

Muhly composed the musical score for the Paris Opera Ballet's production of Clear, Loud, Bright, Forward choreographed by Benjamin Millepied.

In 2020 Muhly completed a "virtual premiere" for the San Francisco Symphony during the COVID-19 pandemic, titled Throughline.

[28] In 2021 his composition Shrink appeared on Violinist Pekka Kuusisto's album First Light released by Pentatone.