This study addresses the challenge of optimizing flat-plate solar collector design, traditionally reliant on trial-and-error and simplified engineering design methods. We propose using physics-informed neural networks (PINNs) to predict optimal design conditions in a range of data that not only characterized the highlands of Ecuador but also similar geographical locations. The model integrates three interconnected neural networks to predict global collector efficiency by considering atmospheric, geometric, and physical variables, including overall loss coefficient, efficiency factors, outlet fluid temperature, and useful heat gain. The PINNs model surpasses traditional simplified thermodynamic equations employed in engineering design by effectively integrating thermodynamic principles with data-driven insights, offering more accurate modeling of nonlinear phenomena. This approach enhances the precision of solar collector performance predictions, making it particularly valuable for optimizing designs in Ecuador’s highlands and similar regions with unique climatic conditions. The ANN predicted a collector overall loss coefficient of 5.199 W/(m2·K), closely matching the thermodynamic model’s 5.189 W/(m2·K), with similar accuracy in collector useful energy gain (722.85 W) and global collector efficiency (33.68%). Although the PINNs model showed minor discrepancies in certain parameters, it outperformed traditional methods in capturing the complex, nonlinear behavior of the data set, especially in predicting outlet fluid temperature (55.05 °C vs. 67.22 °C).