Lu hailed from Dongcheng 東城 (modern Xuchi 盱眙, Anhui) and served the warlord Yuan Shu 袁術 before he joined Zhou Yu 周瑜, who recommended him to Sun Quan. In 208, when the northern warlord Cao Cao 曹操 threatened to conquer the south, all general of Sun Quan suggested submitting to Cao Cao, yet Lu Su alone proposed an alliance with Liu Bei 劉備 in the west to resist Cao Cao. Sun Quan agreed, and Lu Su managed the alliance between the two warlords who consequently defeated Cao Cao in the battle of the Red Cliff (Chibi 赤壁, modern Puqi 蒲圻, Hubei).
After Zhou Yu's death, Lu Su took over the command in the west as General of Advancing Martiality (fenwu jiangjun 奮武將軍). He was appointed governor (taishou 太守) of the commandery of Hanchang 漢昌 and awarded the titles of Determined General (pian jiangjun 偏將軍) and General Connecting the Yangtze (hengjiang jiangjun 橫江將軍). He died in office in 217.