The aim of this study was to carry out a systematic review and meta-analysis of the effects of caffeine supplementation on physiological responses to submaximal exercise. A total of 26 studies met the inclusion criteria of adopting double-blind, randomized crossover designs that included a sustained (5–30 min) fixed-intensity bout of submaximal exercise (constrained to 60–85% maximal rate of oxygen consumption) using a standard caffeine dose of 3–6 mg·kg−1 administered 30–90 min prior to exercise. Meta-analyses were completed using a random-effects model, and data are presented as raw mean difference (D) with associated 95% confidence limits (CLs). Relative to placebo, caffeine led to significant increases in submaximal measures of minute ventilation (D = 3.36 L·min−1; 95% CL, 1.63–5.08; P = .0001; n = 73), blood lactate (D = 0.69 mmol·L−1; 95% CL, 0.46–0.93; P < .00001; n = 208), and blood glucose (D = 0.42 mmol·L−1; 95% CL, 0.29–0.55; P < .00001; n = 129). In contrast, caffeine had a suppressive effect on ratings of perceived exertion (D = −0.8; 95% CL, −1.1 to −0.6; P < .00001; n = 147). Caffeine had no effect on measures of heart rate (P = .99; n = 207), respiratory exchange ratio (P = .18; n = 181), or oxygen consumption (P = .92; n = 203). The positive effects of caffeine supplementation on sustained high-intensity exercise performance are widely accepted, although the mechanisms to explain that response are currently unresolved. This meta-analysis has revealed clear effects of caffeine on various physiological responses during submaximal exercise, which may help explain its ergogenic action.