Pir Hajjan Shah, the 'gaddi nasheen' of Ghazi Ghulam Shah Mari Dargah, died in Patel Hospital in Karachi, the capital of Sindh.
Shah was admitted to the hospital after he was severely injured in the bomb attack at Shikarpur on February 25.
With his death, the toll in the attack rose to five.
The shrine was packed with visitors when a huge explosion ripped through it last month.
As news of Shah's death spread through Shikarpur, his followers came out on the roads and organised mourning processions.
The Ghazi Ghulam Shah Mari Dargah was bombed just five days after Islamic scholar Sain Hussain Shah was targeted in another bomb attack at Jacobabad in Sindh.
Shah's grandson was killed and 10 others were injured in that attack.