The parish was founded in 1958, with about 1,000 parishioners. They celebrated Masses at the canteen of Convent Green Lane. After 10 years of hard work raising funds, they were ready to build the church. Mr Seng Tuck HOOI, a forward thinking architect who designed the first high rise in Penang (the 11 storey Ambassador Hotel) was appointed Architect for the church project. Construction of the church finished in 1969 and the church was blessed by Gregory Yong, then Bishop of Penang. In the 1990s, the parish community hall named Dewan Holy Spirit and three levels of classrooms were open.
In 2001, the church was closed for renovations to prepare for the dedication ceremony 2 years later. In 2003, the cathedral status was transferred from the former Cathedral of the Assumption to the Cathedral of the Holy Spirit. The Rite Of Dedication was held on 20 January 2003 and the new cathedral was blessed by Antony Selvanayagam, Bishop of Penang.
Currently, the Cathedral of the Holy Spirit is administered by Rev Fr. Joachim Robert (parish priest) and Rev Fr. Francis Anthony (assistant parish priest)