Mulatu led his band while playing vibraphone and conga drums—instruments that he introduced into Ethiopian popular music—as well as other percussion instruments, keyboards, and organs.

He collaborated with many notable artists in both countries, arranging and playing on recordings by Mahmoud Ahmed, and appearing as a special guest with Duke Ellington and his band during a tour of Ethiopia in 1973.

[3] Mulatu recorded Mulatu of Ethiopia (1972) in New York City, but most of his music was released by Amha Eshete's label Amha Records in Addis Ababa, Ethiopia, including several singles, his album Yekatit Ethio Jazz (1974), and six out of the ten tracks on the compilation album Ethiopian Modern Instrumentals Hits.

His Western audience increased when the film Broken Flowers (2005) directed by Jim Jarmusch featured seven of his songs, including one performed by Cambodian-American rock band Dengue Fever.

After meeting the Massachusetts-based Either/Orchestra in Addis Ababa in 2004, Mulatu began a collaboration with the band beginning with performances in Scandinavia in summer 2006 and London, New York, Germany, Holland, Glastonbury (UK), Dublin, and Toronto in 2008.

He served as an Abramowitz Artist-in-Residence at the Massachusetts Institute of Technology, giving lectures and workshops and advising MIT Media Lab on creating a modern version of the krar, a traditional Ethiopian instrument.

[7] On 1 February 2009, Mulatu performed at the Luckman Auditorium in Los Angeles with a band that included Bennie Maupin, Azar Lawrence, and Phil Ranelin.

[8] In 2015, Mulatu began recording with Black Jesus Experience for Cradle of Humanity, which premiered at the Melbourne Jazz Festival in 2016 and was followed by a tour of Australia and New Zealand.