Optimization based on mathematical models has received growing attention in materials science. The first part of the work aims to optimize the photocatalytic activity of CaTiO3 for rhodamine B (RhB) degradation under UV-A irradiation, based on two developed mathematical models. Thirty hydrothermal syntheses of CaTiO3 were carried out according to the Box-Behnken design, considering synthesis temperature (X1), duration (X2), and concentration of shaping agent (X3) as input variables for two different Ca2+ sources: Ca(NO3)2 and CaCl2 (X4). The conversion of the studied pollutant after 4 h was situated in the range of 20–80%. Second-order regression and feedforward backpropagation artificial neural network models were developed, considering the synthesis conditions (X1, X2, X3, X4) as input and the conversion as output variables. The proposed model-based methodology for the optimization of CaTiO3 photocatalytic efficiency finally directed to the experimentally attained value of 96% for 200 °C (X1, opt), 23.17 h (X2, opt), 0.67 M (X3, opt), CaCl2 (X4, opt). Furthermore, in the second part of the study, the morphological, structural, textural, and optical properties of selected CaTiO3 samples were investigated via scanning electron microscopy, X-ray diffractometry, N2 sorption, and diffuse reflectance spectroscopy. Finally, the kinetic parameters for adsorption (kads: 0.10–0.67 m·h−1), desorption (kdes: 79–150 mmol·m−2·h−1), degradation (kdegr: 0.001–0.010 mmol·m−2(1−α)·W−α·h−1), and intensity exponent (α: 0.54–0.55) were fitted using an optimization procedure, considering the experimentally determined and model-predicted apparent reaction rate constants. The obtained kinetic parameters were correlated with the specific surface area of the catalysts and the conversion of RhB.