Monkeypox, caused by monkeypox virus (MPXV), has become a global public health concern; however, the T-cell immunity against MPXV following smallpox vaccination remains unclear. In this study, we screened the immunogenicity of 21 predicted MPXV epitopes and compared immune responses between young and elderly groups. Two immunogenic CD8⁺ T-cell epitopes, M15 and M17, were identified, both of which effectively stimulated specific immune responses, with significantly stronger responses observed in the young group. Notably, this study provides the first evidence that smallpox vaccination induces CD8⁺ T-cell immunity that cross-recognizes the MPXV epitopes M15 and M17 and remains detectable for more than four decades after vaccination, as demonstrated in vaccinated individuals aged 53–75. These findings provide experimental evidence for understanding the cross-protective mechanisms of the smallpox vaccine and informing monkeypox vaccine development.