The Southwest Florida shelf encompasses diverse and essential marine ecosystems that provide a variety of socioecological services and support commercial and recreational fisheries. Compounding global and local stressors have led to habitat degradation, declining water quality, and episodic extreme events, with cascading ecosystem impacts. The Florida Regional Ecosystems Stressors Collaborative Assessment (FRESCA) is a collective effort to evaluate five key stressors affecting the region. This multidisciplinary project takes a comprehensive approach to monitoring, predicting, and managing South Florida waters through observation, experimentation, and modeling. Evaluating the combined effects of fluctuations in key stressors on target species is necessary for informed decision-making with a long-term outlook. To support major ongoing restoration efforts in the area, we explore the relationships of these stressors to the abundance and distribution of the fish community. These linkages are used to forecast species’ shifts under alternative climate scenarios and restoration strategies for proactive management. We apply spatiotemporal species distribution modeling to quantify potential shifts in abundance and distribution under key stressors, including ocean acidification, hypoxia, ocean warming, harmful algal blooms, and eutrophication. Regional ocean modeling provides physical and biogeochemical parameters for historical reconstructions and future projections and serves as the primary environmental inputs for species distribution modeling. Additionally, observational and experimental data from the broader collaboration are integrated to provide context and complement modeled estimates. Collectively, this multi-stressor, interdisciplinary approach provides a holistic view of historical fish species distribution and potential responses to environmental change in South Florida waters.