The study identified four variants of bla CTX-M (CTX-M-15, CTX-M-55, CTX-M-64, and CTX-M-65) in extended-spectrum cephalosporin-resistant Escherichia coli from livestock and in-contact humans in Southeast Nigeria. Other AMR genes such as bla TEM-1b, aac 3-IId, qnr S1, and sul 2 were also characterized.