Given the limitation of available antiviral drugs and vaccines, there remains to be a pressing need for novel anti-influenza drugs. Rupestonic acid derivatives were reported to have an anti-influenza virus activity, but their mechanism remains to be elucidated. Herein, we aim to evaluate the antiviral activity of YZH-106, a rupestonic acid derivative, against a broad-spectrum of influenza viruses and to dissect its antiviral mechanisms. Our results demonstrated that YZH-106 exhibited a broad-spectrum antiviral activity against influenza viruses, including drug-resistant strains in vitro. Furthermore, YZH-106 provided partial protection of the mice to Influenza A virus (IAV) infection, as judged by decreased viral load in lungs, improved lung pathology, reduced body weight loss and partial survival benefits. Mechanistically, YZH-106 induced p38 MAPK and ERK1/2 phosphorylation, which led to the activation of erythroid 2-related factor 2 (Nrf2) that up-regulated heme oxygenase-1 (HO-1) expression in addition to other genes. HO-1 inhibited IAV replication by activation of type I IFN expression and subsequent induction of IFN-stimulated genes (ISGs), possibly in a HO-1 enzymatic activity-independent manner. These results suggest that YZH-106 inhibits IAV by up-regulating HO-1-mediated IFN response. HO-1 is thus a promising host target for antiviral therapeutics against influenza and other viral infectious diseases.