- Epidemic spread in single-host systems strongly depends on the population’s transmission network. However, little is known regarding the spread of epidemics across networks representing populations of multiple hosts. We explored cross-species transmission in a multilayer network where layers represent populations of two distinct hosts, and disease can spread across intralayer (within-host) and interlayer (between-host) edges. We developed an analytic framework for the SIR epidemic model to examine the effect of (i) source of infection and (ii) between-host asymmetry in infection probabilities, on disease risk. We measured risk as outbreak probability and outbreak size in a focal host, represented by one network layer. Numeric simulations were used to validate the analytic formulations. We found that outbreak probability is determined by a complex interaction between source of infection and between-host infection probabilities, whereas outbreak size is mainly affected by the non-focal host to focal host infection probability. Hence, inter-specific asymmetry in infection probabilities shapes disease dynamics in multihost networks. These results highlight the importance of considering multiple measures of disease risk and advance our understanding of disease spread in multihost systems. The study provides a flexible way to model disease dynamics in multiple hosts while considering contact heterogeneity within and between species. We strongly encourage empirical studies that include information on both cross-species infection rates and network structure of multiple hosts. Such studies are necessary to corroborate our theoretical results and to improve our understanding of multihost epidemiology.