Addressing the pivotal challenge of lattice distortion and electronic structure modulation in High-Entropy Alloys (HEAs) for electrochemical catalysis, this investigation presents the synthesis of a novel PtRhNiCoFeGaW HEA in a three-dimensional nanoflower configuration. This design strategically combines enhanced morphological features and a synergistic metallic interaction, propelling the catalytic efficiency forward in methanol and formic acid oxidation reactions (MOR and FAOR). The synthesized HEA nanoflowers exhibit superior mass and specific activities of up to 1.34 mA μgPt−1 and 4.43 mA cm−2 for MOR, alongside 0.52 mA μgPt−1 and 1.74 mA cm−2 for FAOR, markedly surpassing those of conventional Pt/C and PtRhNi NFs. This leap in performance is primarily attributed to the intricate elemental synergy within the HEAs, which effectively minimizes CO poisoning (a notorious catalyst deactivator) by improving CO* resistance. Furthermore, the study delineates how the unique nanoflower morphology contributes to exposing a plethora of active sites, thereby maximizing catalytic action. This research not only navigates through the complexities of crafting multi-elemental catalytic systems but also establishes a foundational strategy for developing next-generation HEA-based electrocatalysts, poised to significantly impact future advancements in energy conversion technologies.