Human infections with avian influenza A (H10N3) have recently been reported, representing a notable global public health concern. To seek effective strategies for emerging H10N3 virus infection and provide tools for vaccine and antiviral drugs development, we established a mouse model with a novel human-derived H10N3 virus. Our findings revealed that this human-derived H10N3 virus was highly lethal to C57BL/6J, ICR, and BALB/c mice. Neuraminidase inhibitors (oseltamivir or peramivir) effectively conferred protection for H10N3 low-lethal infection, but the efficacy of peramivir is superior to that of oseltamivir. One single dose of baloxavir marboxil (BM) treatment at 2 h post-infection provides complete protection against mortality, but BM treatment with a 24h delay has no protective effect against mortality caused by H10N3 virus infection. Furthermore, BM multiple doses treatment with a 24h delay for H10N3 infection remains effective in preventing weight loss and enhancing viral clearance, but its protective efficacy against mortality was significantly attenuated. However, both in vitro and in vivo combination of BM with NAIs exhibit significant additive effect against H10N3 virus infection than BM or NAIs monotherapy. Our findings suggest that combination of BM with NAIs represents a promising therapeutic strategy for emerging H10N3 infections in clinical practice.