He was born in Nakasongola District on 5 July 1952. He attended local elementary and secondary schools. He studied at Makerere University earning the combined degree/diploma of Bachelor of Arts with the Diploma in Education (BA.Dip.Ed.) in 1975. In 1987, he earned the Certificate in Hotel Management, from an undisclosed institution in Tripoli, Libya
For eleven years, from 1975 until 1986, Muruli Mukasa was a teacher; for the last two years he was the principal of the school where he taught. Since 1989, he has been a member of parliament, representing his home constituency. He was appointed Minister of Security in May 2011. He replaced Amama Mbabazi, who was appointed Prime Minister of Uganda.
In addition to his docket of Security, Mukasa has served as Minister for Kampala, before a substantive minister was appointed in 2011 and in 2014, when the line Minister, Frank Tumwebaze, took a leave of absence. In a cabinet reshuffle on 1 March 2015, he was transferred to the post of Minister of Gender and Social Issues, replacing Mary Karooro Okurut, who was named Minister for Security.