The present study aims to investigate effects of caffeine ingestion and sex difference on muscle performance, delayed-onset muscle soreness (DOMS), and various biomarkers under exercise-induced muscle damage (EIMD). Twenty (10 male and 10 female) healthy elite college athletes were recruited. Participants ingested either caffeine (6 mg/kg) or a placebo in a randomized, double-blind, and counterbalanced fashion at 24 and 48 h following EIMD. Muscle performance, DOMS, and blood samples were taken an hour before and an hour after supplementation. Caffeine ingestion restored impaired maximal voluntary isometric contractions (MVIC: 10.2%; MVICpost: 7.2%, both P < 0.05) during EIMD across both sexes. Following caffeine ingestion during MVIC, while affected by EIMD, an interaction was found in DOMS and serum K+ (both P < 0.05), with males showing greater attenuation (21.5 and 16.9%, respectively) compared with females (4.6 and 1.3%, respectively). DOMS demonstrated an inverse correlation with MVIC after caffeine ingestion both overall and among male athletes (r = -0.34 and -0.54, respectively; P < 0.05) but not among female athletes (r = -0.11; P > 0.05) under EIMD. In addition, caffeine ingestion increased postexercise serum glucose and lactate concentrations across both sexes (both P < 0.05). This is the first study to show that male athletes, compared with female athletes, experience a greater reduction in DOMS during enhanced MVIC when caffeine was consumed, suggesting men might receive greater ergogenic effects from caffeine when affected by EIMD. Furthermore, caffeine ingestion was able to restore impaired muscle power among elite collegiate athletes across both sexes. NEW & NOTEWORTHY Exercise-induced muscle damage (EIMD) reduces anaerobic/aerobic performance and increases delayed-onset muscle soreness (DOMS) during exercise. We show that acute caffeine supplementation at a dosage of 6 mg/kg seems to facilitate recovery of anaerobic muscle power and attenuate DOMS after EIMD across both sexes. Furthermore, male athletes, compared with female athletes, when caffeine was prescribed, experience a greater reduction in DOMS with better restoration of impaired maximal voluntary isometric contractions. This suggests that male athletes might benefit from the ergogenic effect of acute caffeine supplementation after the onset of EIMD.