Since the first emergence of highly pathogenic avian influenza (HPAI) H5N1 viruses in dairy cattle, the virus has continued to spread, reaching 17 states and at least 1000 dairy herds in the United States. Subsequently, spillovers of the virus from dairy cattle to humans have been reported. Pigs are an important host in influenza ecology because they serve as a mixing vessel in which novel reassortant viruses with pandemic potential can be generated. Here, we show that oro-respiratory infection of pigs resulted in productive replication of a bovine-derived HPAI H5N1 B3.13 virus. Infectious virus and viral antigen were mainly identified in the lower respiratory tract of principal infected pigs, and sero-conversion was observed in most of the principal pigs at later time points, suggesting replication of the bovine-derived HPAI H5N1 B3.13 virus in pigs. In one animal, we detected the emergence of a mutation in the hemagglutinin (HA) previously associated with increased affinity for “mammalian-type” α2,6-linked sialic acid receptors, but this mutation did not reach majority consensus levels. Sentinel contact pigs remained sero-negative throughout the study, indicating lack of transmission. These results support that pigs are susceptible to a bovine-derived HPAI H5N1 B3.13 virus, but this virus did not replicate as robustly in pigs as swine-adapted influenza viruses.