Annual vaccination is not effective in conferring cross-protection against antigenically different influenza viruses. Therefore, it is of high priority to improve the cross protective efficacy of influenza vaccines. We investigated the adjuvant effects of monophosphoryl lipid A (MPL) and oligodeoxynucleotide CpG (CpG) on promoting homologous protection and cross-protection after vaccination of C57BL/6 and BALB/c mice with inactivated split virus. Combination adjuvant effects of MPL and CpG on improving homologous and cross protective vaccine efficacy were evident as shown by higher levels of homologous and cross-reactive binding IgG and hemagglutination inhibiting antibodies. Combination adjuvant effects on enhancing the protective efficacy against homologous and heterosubtypic virus were demonstrated by less weight loss, lower airway inflammatory disease, and better control of viral loads as well as prevention of inflammatory cytokines and cellular infiltrates. Overall, the findings in this study suggest that a combination adjuvant of different toll-like receptor ligands exhibits a unique pattern of innate and adaptive immune responses, contributing to improved homologous and heterosubtypic cross-protection by inactivated split virion influenza vaccination.