Abstract: Seasonal influenza caused by the influenza virus poses a serious threat to human health. The rapid emergence of drug-resistant viral strains and the increasing incidence of novel infectious diseases underscore the urgent need for researchers to develop innovative anti-influenza strategies and drugs. The identification of effective drug combinations and the repurposing of existing drugs have gained traction as a potential avenue for antiviral therapy. This study employed a high-throughput screening system for influenza A virus (IAV) inhibitors to identify drug combinations that exhibit synergistic effects with baloxavir marboxil from FDA-approved and pharmacopeia-listed compound libraries. The results showed that triprolidine, hydroquinine, and mexenone, which individually display limited anti-influenza activity, exhibited synergistic effects when combined with baloxavir marboxil markedly enhancing its anti-IAV potency in cells. Mechanistic studies indicated the synergistic effects of these drug combinations with baloxavir marboxil were not attributed to the inhibition of IAV RNA dependent RNA polymerase (RdRp) activity, suggesting that alternative mechanisms may be responsible for their enhanced effects. This study provides preliminary evidence supporting the feasibility of this drug combination screening strategy and offers a theoretical basis for improving the therapeutic potential of baloxavir marboxil through combination therapy.