Our understanding of the factors underlying the evolutionary success of different lineages of pandemic Vibrio cholerae remains incomplete. Interestingly, two unique genetic signatures define the West African South American (WASA) lineage of V. cholerae responsible for the 1991-2001 Latin American cholera epidemic. Here we show these signatures encode diverse anti-phage defence systems. Firstly, the WASA-1 prophage encodes a 2-gene abortive-infection system WonAB that renders the lineage resistant to the major predatory vibrio phage ICP1, which alongside other phages, restricts cholera epidemics and has potential for use in prophylaxis. Secondly, the unique set of genes on Vibrio seventh pandemic island II encodes an unusual modification-dependent restriction system and a new type of the Shedu defence family. Taken together, we propose that these anti-phage defence systems have likely contributed to the success of a major epidemic lineage of the ongoing seventh cholera pandemic.