In this study, a three-dimensional numerical model was developed to investigate the influence of obstacles on the hydrodynamic behavior of a serpentine flow field. Various obstacle geometries (rectangular, trapezoidal, triangular, and cylindrical), quantities (1–3 blocks), and positions (straight vs. curved channel sections) were systematically analyzed. Results show that rectangular obstacles enhance mean velocity but significantly increase pressure drop and reduce flow uniformity. In contrast, trapezoidal and cylindrical shapes offer a more balanced tradeoff, achieving improved uniformity and flow enhancement with moderate hydraulic penalties. Increasing obstacle number improves electrolyte velocity uniformity across all cases, though diminishing returns are observed beyond two blocks. Importantly, placing obstacles in curved sections of the serpentine field yields up to 9% higher uniformity compared to straight placements, without increasing pressure loss—leveraging pre-existing low-velocity regions to enhance distribution. These findings align with previous literature and highlight that optimized obstacle shape, number, and positioning can significantly improve mass transport and flow distribution in vanadium redox flow batteries (VRFBs). To complement the computational fluid dynamics (CFD) analysis, an artificial neural network (ANN) was trained to predict pressure drop using key geometric and flow features as inputs. The ANN demonstrated excellent agreement with numerical results and reduced the computational time required to obtain the results by 6 orders of magnitude.