This study focuses on the utilization of connectionist models, specifically Independent Component Analysis (ICA), Genetic Algorithm (GA), Particle Swarm Optimization (PSO), and Genetic Algorithm-Particle Swarm Optimization (GAPSO) integrated with a least-squares support vector machine (LSSVM) to forecast the degradation of tetracycline (TC) through photocatalysis using Metal-Organic Frameworks (MOFs). The primary objective of this study was to evaluate the viability and precision of these connectionist models in estimating the efficiency of TC degradation, particularly within the context of wastewater treatment. The input parameters for these models cover essential MOF characteristics, such as pore size and surface area, along with critical operational factors, such as pH, TC concentration, catalyst dosage, and illumination duration, all of which are linked to the photocatalytic performance of MOFs. Sensitivity analysis revealed that the illumination duration is the primary influencer of TC photodegradation with MOF photocatalysts, while the MOFs’ surface area is the second crucial parameter shaping the efficiency and dynamics of the TC-MOF photocatalytic system. The developed LSSVM models display impressive predictive capabilities, effectively forecasting the experimental degradation of TC with high accuracy. Among these models, the GAPSO-LSSVM model excels as the top performer, achieving notable evaluation metrics, including STD, RMSE, MSE, MRE, and R2 at values of 3.09, 3.42, 11.71, 5.95, and 0.986, respectively. In comparison, the PSO-LSSVM, ICA-LSSVM, and GA-LSSVM models yield mean relative errors of 6.18%, 7.57%, and 11.37%, respectively. These outcomes highlight the exceptional predictive capabilities of the GAPSO-LSSVM model, solidifying its position as the most accurate and dependable model for predicting TC photodegradation in this study. This study contributes to advancing photocatalytic research and effectively reinforces the importance of leveraging machine learning methodologies for tackling environmental challenges.