The design and optimization of thermal processing of solid-liquid food mixtures, such as canned mussels, requires the knowledge of the thermal history at the slowest heating point. In general, this point does not coincide with the geometrical center of the can, and the results show that it is located along the axial axis at a height that depends on the brine content. In this study, a mathematical model for the prediction of the temperature at this point was developed using the discrete transfer function approach. Transfer function coefficients were experimentally obtained, and prediction equations fitted to consider other can dimensions and sampling interval. This model was coupled with an optimization routine in order to search for different retort temperature profiles to maximize a quality index. Both constant retort temperature (CRT) and variable retort temperature (VRT; discrete step-wise and exponential) were considered. In the CRT process, the optimal retort temperature was always between 134 °C and 137 °C, and high values of thiamine retention were achieved. A significant improvement in surface quality index was obtained for optimal VRT profiles compared to optimal CRT. The optimization procedure shown in this study produces results that justify its utilization in the industry.