Objective: Caffeine is a central nervous system stimulant that can effectively alleviate brain fatigue and low cognitive efficiency induced by total sleep deprivation (TSD). Recent studies have demonstrated that caffeine can improve subjective attention and objective behavioral metrics, such as arousal level, reaction time, and memory efficiency. However, only a few studies have examined the electrophysiological changes caused by the caffeine in humans following sleep disturbance. In this study, an event-related potential (ERP) technique was employed to measure the behavioral, cognitive, and electrophysiological changes produced by caffeine administration after TSD. Methods: Sixteen healthy subjects within-subject design performed a visual Go/No-Go task with simultaneous electroencephalogram recording. Behavioral and ERP data were evaluated after 36 h of TSD, and the effects of ingestion of either 400 mg of caffeine or placebo were compared in a double-blind randomized design. Results: Compared with placebo administration, the Go hit rates were significantly enhanced in the caffeine condition. A simple effect analysis revealed that, compared with baseline, the Go-P2 amplitude was significantly enhanced after TSD in the caffeine consumption condition. A significant main effect of the drug was found on No-Go-P2, No-Go-N2 amplitude, and Go-P2 latency before and after TSD. Conclusion: Our findings indicate that caffeine administration has acute effects on improving the efficiency of individual automatic reactions and early cognitive processes. Caffeine was related to the preservation of an individual's arousal level and accelerated response-related decisions, while subjects' higher-level recognition had limited improvement with prolonged awareness.