The electrocatalytic oxygen evolution reaction (OER) requires stable, highly active, and robust earth-abundant electrocatalysts. In the present study, we combine theoretical simulations with experimental approaches to design and synthesize NiFeW layered double hydroxide (LDH) for efficient OER in alkaline electrolytes. Density functional theory with the Hubbard U (DFT + U) calculations suggests that W, a high-valence metal, can improve the catalytic activity of Fe sites and optimize adsorption energies for OER intermediates at the surface of NiFeW LDH. Electrochemical measurements of the as-synthesized NiFeW LDH with a constant mass loading reveals that the LDH with the NiFeW molar ratio of 4:1:1 presented the highest intrinsic OER activity among all bi- and trimetallic LDH catalysts in this study. Furthermore, the nanostructures with the optimal active metal molar ratio are in situ grown on hydrophilic-treated carbon paper to fabricate an integrated 3D electrode with an overpotential of 248 mV at the catalytic current density of 20 mA cm−2 and a low Tafel slope of 68 mV dec−1 in 1.0 M KOH solution. This indicates that NiFeW LDH is among the most active NiFe-based OER electrocatalysts reported to date. X-ray photoelectron spectroscopy and elemental analysis confirm that the optimized Ni Fe W LDH presents a stable chemical composition and Ni, Fe, and W are still present in the catalyst after alkaline OER measurements. These findings offer new insights and avenues for the future design and study of stable and active multi-metal-based OER electrocatalysts.