Cationic substitution was investigated as a strategy to increase the electrocatalytic activity of IrO 2 -based films for the oxygen evolution reaction (OER). For this purpose, an approach that combines detailed experimental characterization with quantum mechanical calculations based on density functional theory was employed. A series of (100)-oriented Ir 1−x M x O 2 thin films, with M = Ni, Cr, Mo, W, Sn, Pt, Rh, Ru, V, and Mn, was prepared with a one-step synthesis approach based on pulsed laser deposition, and the electrocatalytic activity of these films for the OER was measured. Matching material compositions and structures were generated in silico for DFT-based calculations of their electronic structure and OER pathway. A comparison of the experimental and theoretical results revealed the viable activity descriptor, paving the way for a systematic search to find the most active Ir-based OER catalyst.