Lower trophic level processes are integral to proper functioning of large aquatic ecosystems and have been disturbed in Lake Ontario by various stressors including exotic species. The invasion of benthic habitats by dreissenid mussels has led to systemic changes and native faunal declines. Size-dependent physiological rates, spatial differences and connectivity, competition, and differential population dynamics among invertebrate groups contributed to the change and system complexity. We developed a spatially explicit, individual-based mechanistic model of the benthic ecosystem in Lake Ontario, with coupling to the pelagic system, to examine ecosystem dynamics and effects of dreissenid mussel invasion and native fauna losses. Benthic organisms were represented by functional groups; filter-feeders (i.e., dreissenid mussels), surface deposit-feeders (e.g., native amphipod Diporeia spp.), and deposit-feeders (e.g., oligochaetes and other burrowers). The model was stable, represented ecological structure and function effectively, and reproduced observed effects of the mussel invasion. Two hypotheses for causes of Diporeia loss, competition or disease-like mortality, were tested. Simple competition for food did not explain observed declines in native surface deposit-feeders during the filter-feeder invasion. However, the elevated mortality scenario supports a disease-like cause for loss of the native amphipod, with population changes in various lake areas and altered benthic biomass transfers. Stabilization of mussel populations and possible recovery of the native, surface-deposit feeding amphipod were predicted. Although further research is required on forcing functions, model parameters, and natural conditions, the model provides a valuable tool to help managers understand the benthic system and plan for response to future disruptions.