Regular physical activity confers health benefits and improves the general quality of life. Recently, alkaline-reduced water (ARW) consumption has garnered increasing attention in the field of sports. ARW effectively inhibits the oxidative stress generated in cells during high-intensity exercises; however, whether it exerts similar effects during exhaustive exercises remains unknown. This study was designed as a randomized, controlled, crossover, double-blind clinical trial with a single intervention of ARW intake (pH 9.5, 10 mL/kg body weight) after intense exercise. The participants were divided into two groups, wherein they consumed either purified water (PW group) or ARW (ARW group). Blood samples were collected before exercise, immediately after exercise, and 15 min after drinking water. The serum levels of oxidative stress markers and fatigue markers were determined. The results showed that ROS (p < 0.01) and NO levels (p < 0.001) were significantly decreased after ARW intake, and the reduction was more pronounced than that in the PW group. Interestingly, the increase in GPx and MDA levels was mediated by ARW intake (both p < 0.05) after exercise. The levels of fatigue markers, such as lactate (p < 0.001), lactate dehydrogenase (p < 0.001), and phosphate (p < 0.001), were significantly reduced in both groups, with ARW intervention showing more decreased markers. The correlation analysis results showed that ARW may help maintain homeostatic conditions for ROS, antioxidant systems, and fatigue markers. These findings indicate that ARW consumption is effective in reducing oxidative stress and fatigue following exhaustive exercise and that ARW could be used as an antioxidant and anti-fatigue supplement after exhaustive physical exercise.