Caffeine intake results in a decrease in perception of effort, but the cortical substrates of this perceptual effect of caffeine are unknown. The aim of this randomized counterbalanced double-blind crossover study was to investigate the effect of caffeine on the motor-related cortical potential (MRCP) and its relationship with rating of perceived effort (RPE). We also investigated whether MRCP is associated with the increase in RPE occurring over time during submaximal exercise. Twelve healthy female volunteers performed 100 intermittent isometric knee extensions at 61 ± 5% of their maximal torque 1.5 h after either caffeine (6 mg/kg) or placebo ingestion, while RPE, vastus lateralis electromyogram (EMG), and MRCP were recorded. RPE and MRCP amplitude at the vertex during the first contraction epoch (0–1 s) were significantly lower after caffeine ingestion compared with placebo (P <0.05) and were significantly higher during the second half of the submaximal intermittent isometric knee-extension protocol compared with the first half (P <0.05). No significant effects of caffeine and time-on-task were found for EMG amplitude and submaximal force output variables. The covariation between MRCP and RPE across both caffeine and time-on-task (r10 = −0.335, P <0.05) provides evidence in favor of the theory that perception of effort arises from neurocognitive processing of corollary discharges from premotor and motor areas of the cortex. Caffeine seems to reduce perception of effort through a reduction in the activity of cortical premotor and motor areas necessary to produce a submaximal force, and time-on-task has the opposite effect.