Direct urea fuel cells (DUFCs) are proven as environmentally benign energy generation devices and hold superior potential to meet the booming energy demand with the use of waste‐water containing urea/urine as a fuel. Despite the high theoretical gravimetric energy density, DUFC's experimentally projected value is substantially lower, due to the sluggish electrokinetics of urea oxidation reaction (UOR). The key to realizing high performance, durable DUFCs is reliant upon the advancement of electrode materials encompassing electrochemically active and stable UOR nanocatalysts. Furthermore, an in‐depth electromechanistic understanding of UOR and the use of human urine as a fuel are of great importance to the scale‐up objectives of DUFCs. Herein, the comprehensive portrayal of these salient aspects along with the scientific breakthroughs of UOR catalysts applicable to DUFCs is essential for the practical augmentation of DUFCs. Accordingly, a comprehensive portrayal of background overview, operating principles, UOR mechanism, and recent advances made on UOR catalysts, with the fundamental aspects of electrochemistry and fuel cells, as well as the critical challenges of existing UOR catalysts is presented. Also, the research and scale‐up challenges of UOR catalysts‐equipped DUFCs are outlined with futuristic perspectives to enhance their viability in sustainable energy generation.