The Quaid-i-Azam remained closely associated with it till the end of his life. In fact, his association with College goes back to the last decade of the last century when he was a student of the Sindh Madressah-tul-Islam. On the occasion of the inception of the college on June 21, 1943, the Quaid-i-Azam Muhammad Ali Jinnah who was at that time the President of All India Muslim League, delivered his speech in which he said:

Dr. Amir Hassan Siddiqui was the first principal of the Sindh Muslim College and was also a member of the Aligarh Muslim university teaching staff. He held the post till 1947 for two years thereafter the principal-ship was held by the vice principal Prof. S.J. Wasti and Prof. A.M. Maulvi, in 1949, Prof. Syed Ghulam Mustafa Shah, an old student of Sindh Madressah and the Aligarh Muslim University. He also served as the staff of the college for a long time. He served the institution with zeal, ability, courage and selfless devotion. Prof. Syed Ghulam Mustafa Shah was succeeded by Prof. Abdul Sattar Kohati who had a long association with the institution. Prof. Hashmatullah Lodi had the honour of being the last principal of the undivided S. M College.

The science section, which started functioning in 1945, was situated in a separate building at a distance of nearly a mile from Arts College, it was difficult to manage the matters of the college with one principal from that long distance and, on account of its huge enrollment of some 1500 students in science faculty alone. The government of Sindh on nationalization bifurcated the S.M Govt. College with the minimum loss of time and granted the status of a separate science college on 1^st September, 1972.

Prof. Hashmatullah Lodi again had the honour of being the first Principal of Sindh Muslim Govt. Science College. Prof. Lodhi who had a long association with the college was devoted to the cause of education.

Prof. Syed Basit Ali took over the charge from prof. Hashmatullah Lodhi and discharged his responsibilities as an acting Principal with great confidence and meticulous care till Prof. Zubair Ahmed took the charge on 10^th May, 1987. Being a senior member of staff with long association to work since 1959, he maintained the best traditions of the college. His inherent qualities led him to be notified as the Principal of the college by the Education Department Govt. Of Sindh.

On 25^th August 1996, Prof. Qari Abdul Razzaq took over the charge from Prof. Zubair Ahmed. On 3^rd December 1999, Prof. Dr. Rafique Ahmed Siddiqui was made the Principal for a short period. On this appointment as Director of College Education Sukkur, prof. Syed Fahim Ahmed, a senior teacher of the college, took the official charge of the Principal on March 15, 2000. He served the college to the best of his abilities till December 20, 2000. Then Prof. Jamil Ahmed, another senior teacher of the college, was notified as the Principal by Sindh Education department. Thereafter, on 29 April 2008 Prof. Ishrat Mian became the Principal for a short period of time. The same year, in 2008, Prof. Zaibun-Nisa Siddqui took charge and became the Principal. She served the college to the best of ability. Then, on 3-5-2010, Prof. Hamida Mangi became the Principal and remained in the office till 5^th November, 2010.