A local of Yicheng, Xiangyang (present-day Yicheng, Hubei), Ma Su was one of the five brothers in the family, all of whom were renowned for their intellects and commonly known as the "Five Changs" as their style names all contained "Chang". Though Ma Su's elder brother Ma Liang was deemed to be the most talented among them all. Together with Ma Liang, Ma Su began his service under Liu Bei around 205, when Liu Bei was still a guest of Liu Biao in Jing Province (covering present-day Hubei and Hunan). In 214, when Liu Bei started his campaign against Liu Zhang into Yi Province, Ma Su followed him with the army and served as a military advisor along with Pang Tong and Fa Zheng. Ma Su must have done well since after Liu Bei's victory, he was named as the Magistrate of Mianzhu and Chengdu the capital of the recently conquered province.