ABSTRACT This study aimed to identify the ecological and spatial correlates of the COVID-19 secondary transmission mechanisms. The dataset comprised cross-province daily COVID-19 cases recorded in Italy from 25 February to 26 May 2020. Several physical and socio-economic variables and a broad set of spatial matrices were employed to explain epidemic spreading. First, the serial transmission interval was identified through autoregressive models. Second, the impact of the ecological and spatial variables on the epidemic’s secondary transmission was analysed by means of ordinary least squares and spatial regression models. The study found that, against widespread belief, the epidemic diffusion was higher in the more affluent and developed territorial units. As for the spatial component, a secondary transmission spatial spillover emerged. Contiguity and distance but also mobility fluxes proved to be significant in this transmission. This study’s contribution is methodological and empirical. As for methodology, it shows that spatial models can be used not only to identify epidemic localisation but also to predict epidemic transmission, provided the problem of the multidirectional nature of spatial dependence is adequately dealt with. Moreover, this study shows that no satisfactory understanding of the epidemic would be achieved without considering both ecological and spatial determinants. As for the empirical aspect, it was found that the main contribution to epidemic spreading came from the anthropologic context rather than the physical one. In particular, direct and indirect indicators of mobility, transport and social interaction emerged as crucial for the epidemic transmission.