Fermentation is one of the oldest methods to assure the safety and quality of foods, and to prolong their shelf life. However, a successful fermentation relies on the correct kinetics depending on some factors (i.e., ingredients, preservatives, temperature, inoculum of starter cultures). Predictive microbiology is a precious tool in modern food safety and quality management; based on the product characteristics and the conditions occurring in food processing, the inactivation of or increase in microbial populations could be accurately predicted as a function of the relevant intrinsic or extrinsic variables. The main aim of this study was the optimization of the formula of a smoked fermented fish product using predictive modeling tools (tertiary and secondary models) in order to define the role of each factor involved in the formulation and assure a correct course of fermentation. Product optimization was conducted through the software Food Spoilage and Safety Predictor (FSSP), by modeling the growth of lactic acid bacteria (LAB) as a function of some key parameters such as temperature, pH, salt, liquid smoke, carbon dioxide, and nitrites. The variables were combined through a fractional design of experiments (DoE) (3k-p), and the outputs of the software, i.e., the maximal growth rate (μmax) and the time to attain the critical threshold (tcrit), were modeled through a multiple regression procedure. The simulation, through FSSP and DoE, showed that liquid smoke is the most critical factor affecting fermentation, followed by temperature and salt. Concerning temperature, fermentation at 20–25 °C is advisable, although a low fermentation temperature is also possible. Other parameters are not significant.