Purpose: The psychobiological model of endurance performance proposes that the perception of effort is the ultimate determinant of endurance performance. Therefore, any physiological or psychological factor affecting the perception of effort will affect endurance performance. Accordingly, this novel study investigated the effects of a frequently used psychological strategy, motivational self-talk (ST), on RPE and endurance performance. Methods: In a randomized between-group pretest–posttest design, 24 participants (mean ± SD age = 24.6 ± 7.5 yr, V˙O2max = 52.3 ± 8.7 mL·kg−1·min−1) performed two constant-load (80% peak power output) cycling time-to-exhaustion (TTE) tests, punctuated by a 2-wk ST intervention or a control phase. Results: A group (ST vs Control) × test (pretest vs posttest) mixed-model ANOVA revealed that ST significantly enhanced TTE test from pretest to posttest (637 ± 210 vs 750 ± 295 s, P <0.05) with no change in the control group (486 ± 157 vs 474 ± 169 s). Moreover, a group × test × isotime (0%, 50%, and 100%) mixed-model ANOVA revealed a significant interaction for RPE, with follow-up tests showing that motivational self-talk significantly reduced RPE at 50% isotime (7.3 ± 0.6 vs 6.4 ± 0.8, P <0.05), with no significant difference in the control group (6.9 ± 1.9 vs 7.0 ± 1.7). Conclusions: This study is the first to demonstrate that ST significantly reduces RPE and enhances endurance performance. The findings support the psychobiological model of endurance performance and illustrate that psychobiological interventions designed to specifically target favorable changes in the perception of effort are beneficial to endurance performance. Consequently, this psychobiological model offers an important and novel perspective for future research investigations.