This work aims to design and dynamically simulate a polygeneration system that integrates a solar-assisted desiccant cooling system for residential applications as an alternative to vapor compression systems. The overall plant layout supplies electricity, space heating and cooling, domestic hot water, and freshwater for a single-family townhouse located in the city of Almería in Spain. The leading technologies used in the system are photovoltaic/thermal collectors, reverse osmosis, and desiccant air conditioning. The system model was developed and accurately simulated in the TRNSYS environment for a 1-year simulation with a 5-min time step. Design optimization was carried out to investigate the system’s best configuration. The optimal structure showed a satisfactory total annual energy efficiency in solar collectors of about 0.35 and about 0.47 for desiccant air conditioning. Coverage of electricity, space heating and cooling, domestic hot water, and freshwater was 104.1%, 87.01%, 97.98%, 96.05%, and 100%, respectively. Furthermore, significant ratios for primary energy saving, 98.62%, and CO2 saving, 97.17%, were achieved. The users’ thermal comfort level was satisfactory over the entire year. Finally, a comparison with an alternative coastal site was performed to extend the polygeneration system’s applicability.