Salmonella contamination of low-water activity (aw) foods poses a serious concern worldwide. The present study was conducted to assess the effects of drying conditions, food composition, and water activity on the desiccation tolerance and thermal resistance of S. Enteritidis FUA1946, S. Senftenberg ATCC43845 and S. Typhimurium ATCC13311 in pet food, binder formulation, and skim milk powder. The samples were wet inoculated with the individual Salmonella strains and were equilibrated to aw 0.33 and 0.75, followed by an isothermal treatment at 70 °C. The thermal inactivation data was fitted to the Weibull model. Irrespective of the aw, food composition and physical structure of the selected foods, strain S. Enteritidis FUA1946 displayed the highest desiccation and thermal resistance, followed by S. Senftenberg ATCC43845 and S. Typhimurium ATCC13311. The food matrix and strain type significantly (p < 0.05) influenced the thermal resistance of microorganisms in foods along with aw change during thermal treatments. To further study the effect of food composition, an additional set of experiments using dry inoculation of the resistant Salmonella strain in the low-aw foods was designed. Significant (p < 0.05) matrix-dependent interaction on Salmonella reduction was observed. The water adsorption isotherms of selected low-aw foods were measured at 20 and 70 °C to relate the thermal inactivation kinetics with the change in the aw. The characterization of thermal resistance of the Salmonella serovars in low-aw products with different compositions and aw in this study may be used for the validation of thermal challenge studies.