Non-thermal technologies (NTT) have been primarily studied for obtaining animal-origin products with improved bacteriological stability, aiming to eliminate the main foodborne pathogens associated with outbreaks, e.g., Salmonella spp., Escherichia coli, Campylobacter jejuni, Listeria monocytogenes, Staphylococcus aureus, Bacillus spp., and Clostridium perfringens, but avoiding the use of heat, leading to energy savings. On the other hand, due to the novelty of these technologies, there is a lack of standardization in their use and, consequently, a reduction in the process efficiency and undesirable changes in the physicochemical, nutritional, and sensory characteristics of food. Therefore, there is a need to utilize mathematical approaches for developing the modeling, validation, and optimization of NTT aiming the pathogen inactivation. In this context, the Box-Behnken design (BBD) and the central composite rotatable design (CCRD) have been severely explored due to the possibility of developing second-order polynomial models based on the linear, quadratic and interaction behaviors of the independent variables, but with a lower number of experiments. In this chapter, we summarized the principles and fundamentals of pathogen inactivation using the main NTT, e.g., high-pressure processing (HPP), ultraviolet C radiation (UV-C), high-intensity ultrasound (HIUS), cold atmospheric plasma (CAP) and pulsed electric field (PEF), as well as the principles of use of BBD and CCRD and their recent application for modeling and optimization of the NTT.