Abstract Preferential oxidation of CO in H 2 (PROX) reaction is a promising solution to the on‐board purification of CO‐contaminated H 2 fuel for use in next‐generation proton‐exchange membrane fuel cells (PEMFC). However, achieving high CO selectivity, activity and structural stability across the wide temperature window remains a great challenge. Herein, we fabricate centimeter scale interfacial PROX catalysts grown from nanoporous single‐crystalline Pr 2 O 3 and Nd 2 O 3 monoliths with lattice surface‐deposited Pt clusters at nanoscale. We demonstrate complete and selective removal of CO in H 2 over an unprecedented wide temperature window (253–403 K). The monoliths are integrated with an operational PEMFC to purify the H 2 fuel contaminated with CO (30 ppm) and enable stable power output for >400 h; over two thousand times longer than without. This work demonstrates that the nanoporous single‐crystalline oxide monoliths can simultaneously achieve the stability and overall performance required to realize practically useful PEMFCs.