Trypanosome parasites of the genus Trypanosoma cause African animal trypanosomosis, a devastating livestock disease plaguing sub-Saharan Africa. Unlike many protozoan parasites, these extracellular blood-borne pathogens directly engage the host’s immune system. While the mouse model has provided valuable insights, a comprehensive understanding of the bovine immune response to trypanosomes remains elusive. Addressing immune response in cattle, the most relevant host species, and how it takes part in mitigating the negative impact of the disease could contribute to set up sustainable control strategies. This review summarizes the current knowledge of the immune response in cattle during trypanosomosis. Following a brief overview of infection processes and bovine trypanotolerance, we delved into the key immunological players: cellular and humoral immunity, cytokine regulation, and immune suppression. We discuss how these mechanisms contribute to tolerance or susceptibility to infection, highlighting critical gaps in knowledge that need further investigation.