Continuous engagement of the Ly49H activating receptor with its ligand (m157) in a transgenic mouse expressing m157 (m157‐Tg) results in hyporesponsiveness of Ly49H+ NK cells. The same interaction, during murine cytomegalovirus (MCMV) infection, leads to activation of Ly49H+ NK cells. MCMV infection results in decreased MHC class I (MHC‐I) expression on the infected cell as well as inflammatory responses, both of which do not take place in the uninfected m157‐Tg mouse, potentially allowing for activation of NK cells in the context of MCMV infection. In this study, we demonstrated that viral infection transiently reverses activation receptor‐mediated NK cell hyporesponsiveness in an MHC‐I‐independent mechanism. Furthermore, Ly49H+ NK cells in an MHC‐I‐deficient environment remained hyporesponsive in the context of m157 expression, even when mature WT splenocytes were transferred into m157‐Tg mice in an MHC‐I‐deficient environment. However, the administration of cytokines TNF‐α, IL‐12, and IFN‐β resulted in a partial recovery from activation receptor‐induced hyporesponsiveness. Thus, the release of the aforementioned cytokines during MCMV infection and not the downregulation of MHC‐I expression appears to be responsible for partial resolution of Ly49H receptor‐induced NK cell hyporesponsiveness.