He advocated the expansion of Qin towards the south and personally commanded the campaigns against the states of Shu 蜀 and Ba 巴. Cuo's political opponent Zhang Yi 張儀 did not accept his argument that the conquest of the southern regions would economically support the further expansion of Qin towards the east. Sima Cuo was right in his argument because the conquest of Shu did not only provide grain and tax income to the state of Qin, but also personnel to staff its large armies. Moreover, the region of Ba was an ideal base for the conquest of the state of Chu 楚 along the valleys of the Yangtze River and the River Han 漢.
In 316, King Huiwen 秦惠文王 (r. 338-311) therefore entrusted Sima Cuo and also Zhang Yi with the southern expedition. The army of Shu was heavily defeated in the battle of the Jiameng Pass 葭萌關 (near modern Guangyuan 廣元, Sichuan).
In 310, a second campaign against Shu was necessary because the regional commander Cheng Zhang 陳壯 rebelled against Qin. This campaign was commanded by Sima Cuo, Gan Mao 甘茂 and Zhang Yi.
In 300, Sima Cuo conducted the military campaign against the state of Wei 魏 and forced the king of this state of cede the territory of Henei 河內 and the former capital Anyi 安邑 (near modern Xiaxian 夏縣, Shanxi).
Sima Cuo also realized the large riverine campaign in 280 along the River Fuling 涪陵江 and conquered the region of Qianzhong 黔中, from where Chu was much easier to attack.