The current outbreak of highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype clade 2.3.4.4b in dairy cattle in the United States has affected nearly 900 dairy farms and resulted in at least 39 human infections, putting health authorities and the scientific community on high alert. Here we characterize the virus growth properties and host-pathogen interactions of an isolate obtained from a sick dairy cow in Texas in vitro and in vivo and compare it to an older HPAI isolate. Despite so far being associated with mild disease in human patients, the cattle H5N1 virus showed superior growth capability and rapid replication kinetics in a panel of human lung cell lines in vitro. In vivo, cattle H5N1 exhibited more intense pathogenicity in mice, with rapid lung pathology and high virus titers in the brain, accompanied by high mortality after challenge via different inoculation routes. Additionally, the cattle H5N1 demonstrated efficient antagonism of overexpressed RIG-I- and MDA5-mediated innate antiviral signaling pathways. In summary, this study demonstrates the profound pathogenicity and suggests a potential innate immune escape mechanism of the H5N1 virus isolated from a dairy cow in Texas.