He started his career as a teacher at the young age of 19. The Jallianwala Bagh massacre stirred his soul and left a deep scar on his mind. His conscience revolted and he plunged into the freedom struggle.
The Akali movement of the twenties in Punjab was a source of political awakening amongst the Sikhs and it ran parallel to the national freedom struggle. Many of the prominent political leaders of the Punjab were drawn to it through the Akali struggle of the 1920’s. Soon after, he gave up teaching to join the freedom struggle. He courted arrest for the first time in 1921, and thus began a long drawn series of Jail going pilgrimages, which ended only in 1947 . His spirit of dedication and sincerity of propose brought him to the front rank of the movement and in 1930, he was appointed to the highest religious office of Sikhism i.e. Jathedar of Akel Takth, Amritsar. He worked with veteran leaders like Baba Kharak Singh. During this period, he came into contact with Pandit Jawahar Lal Nehru and their mutual affection and admiration grew over the years into a strong bond of friendship.
During the post independence period, Musafir ji played a significant role in rehabilitating the Congress in Punjab as President of the Punjab Pradesh Congress Committee for 12 years and as an elected member of the Congress Working Committee. He was the Chief Architect of Congress victory at the polls in 1952. His parliamentary association dates back to 1947 when he was elected to the Constituent Assembly. He was elected to the Lok Sabha in 1952 and again in 1957 and 1962. On November 1, 1966 when the new State of Punjab came into being as a result of re-organization, Giani Gurmukh Singh Musafir took over as its Chief Minister. He was least ambitious for this office yet it came to him unsought and unsolicited.
On assumption of the Chief Ministership of Punjab, Giani Gurmukh Singh Musafir brought to his office the luster of an unblemished record of public life, an amiable and cheerful disposition and, a deep faith in the essential goodness of man. His upright handsome bearing and sense of dignity and poise marked him out as a natural leader. He loomed large on the political horizon of Punjab for several decades. Apart from his involvement in politics, he actively participated in literary and cultural activities of Punjab. He was President of the Kendri Punjabi Lekhari Sabha and Punjabi Sahitya Sameekhya Board, for many years. He was also a member of the General Council of the Indian Sahitya Academy.