The efficacy of caffeine ingestion in enhancing aerobic performance is well established. The evidence for caffeine's effects on resistance exercise is mixed and has not fully examined the associated psychological and psychophysiological changes. This study examined acute effects of ingesting a caffeine-containing energy drink on repetitions to failure, the rating of perceived exertion (RPE), and the readiness to invest physical effort (RTIPE) and mental effort during resistance exercise to failure. Thirteen resistance-trained men took part in this double-blind, randomized cross-over experimental study whereby they ingested a caffeinated (179 mg) energy drink or placebo solution 60 minutes before completing a bout of resistance exercise comprising bench press, deadlift, prone row, and back squat exercise to failure at an intensity of 60% 1-repetition maximum. Experimental conditions were separated by at least 48 hours. Participants completed significantly greater repetitions to failure, irrespective of exercise, in the energy drink condition (p = 0.015). Rating of perceived exertion was significantly higher in the placebo condition (p = 0.02) and was significantly higher during lower-body exercises compared with upper-body exercises irrespective of the substance ingested (p = 0.0001). Readiness to invest mental effort was greater with the energy drink condition (p = 0.04), irrespective of time. A significant time × substance interaction (p = 0.036) for RTIPE indicated that RTIPE increased for both placebo and energy drink conditions preingestion to pre-exercise, but the magnitude of increase was greater with the energy drink condition compared with placebo. This resulted in higher RTIPE postexercise for the energy drink condition. These results suggest that acute ingestion of a caffeine-containing energy drink can enhance resistance exercise performance to failure and positively enhance psychophysiological factors related to exertion in trained men.