Pathogen spectrum of Hand, foot and mouth disease (HFMD) has substantially changed in the past decade. How do the co-circulating pathogens interact and the coronavirus disease 2019 (COVID-19) intervene the incidence of HFMD remain unclear. Here, we evaluated the virus-virus interaction (VVI) of EVs using Spearman’s Correlation in Nanchang, China. And the impact of COVID-19 intervention on HFMD incidence was estimated using seasonal autoregressive integrated moving average (ARIMA) models. Enterovirus (EV) serotypes were determined by RT-PCR. From 2019 to 2022, 1321 (57.5%) out of 2296 HFMD cases were EV-positive, in which coxsackievirus A6 (CVA6) and CVA16 were the major pathogens, accounting for 34.0%-59.6% and 14.9%-31.4%, respectively. Our analyses provide strong statistical support for the existence of VVIs among enteroviruses, in which CVA6 negatively interacted with CVA16 and EV-A71, and positive VVI between CVA16 and EV-A71 was observed. While CVA6 has a (albeit inconsistent) seasonal pattern in Nanchang, typically peaking in fall-winter months before COVID-19 epidemic, CVA16 and EV-A71 contemporaneously peaks around May, supporting the epidemiological VVIs among these strains. During the COVID-19 epidemic, the seasonal HFMD epidemic peak was restrained, indicating the COVID-19 intervention had mitigated EV transmission. Moreover, we first figured out the serotypes from other enteroviruses, among them CVA4, CVA2, CVA5 and CVB3 were the major agents accounting for 34.8%, 23.9%, 23.9% and 10.9%, respectively. Taken together, CVA6 and CVA16 were currently the most predominant pathogens negatively interacted with each other in Nanchang, while NPIs of COVID-19 outbreaks interfered the interactions by mitigating their incidence and transmission.