Hand-foot-and-mouth disease (HFMD) is widespread in the world. Severe HFMD can lead to complications like pneumonia, encephalitis, myocarditis, transverse myelitis and even death. Since HFMD is caused by at least 20 types of enteroviruses, there is an urgent need for broad-spectrum antiviral drugs to help control the spread of HFMD outbreaks. Type I interferon (IFN), as an indispensable part of the immune response, plays a key role in the inhibition of the enterovirus replication cycle without species specificity, and regulation of the innate immune system by inducing the activation of the IFN-stimulated genes. Here, the interplay of enteroviruses and type I IFN was systematically summarized, including pathways for the activation and evasion of type I IFN. Besides, we proposed promising anti-enterovirus agents with therapeutic potential.