Thermal inactivation of Salmonella is a critical component of the calculated thermal process to ensure the safety of cooked human and animal products. However, lethality performance standards for meat processing by-products that may harbor Salmonella have not been properly set under the actual conditions of rendering processes. The goal of this study was to evaluate the thermal inactivation parameters for Salmonella in high-fat beef trimmings as a model system for animal food products treated under simulated “worst-case scenario” commercial rendering conditions. Ground high-fat beef trimmings (50% fat) were artificially inoculated with a 108 CFU/g Salmonella cocktail containing human outbreak strains including the highly thermotolerant serotype Salmonella Senftenberg. The meat samples were packaged and immersed in either water or silicon oil at predetermined temperatures ranging from 60 to 121°C (from 140 to 250°F). D-values of Salmonella at each temperature were calculated from the negative inverse slope of the log CFU per gram versus time plot. The z-values were determined from the negative inverse slope of the log D versus temperature plot. The D-values in thermal death curves for low-fat (20%) content materials (between 60 and 95°C) were 2.175, 0.658, 0.237, 1.563, 0.356, 0.284, 0.264, and 0.201 min, whereas materials with 50% fat (between 100 to 121°C) were 0.277, 0.286, 0.159, 0.143, 0.137, and 0.087 min. The z-values for low- and high-temperature schedules were 43.7 and 42.9°C, respectively. Thermal lethality data for Salmonella inactivation in high-fat rendering raw materials will help animal food processors design adequate thermal processing schedules and support critical control points to ensure the safety of final beef-based rendered products.