Guarana (GUA) seed extract, containing caffeine (CAF) and additional bioactive compounds, may positively affect mental performance, but evidence regarding exercise is limited. This investigation assessed acute GUA ingestion compared with CAF on endurance performance. Eleven endurance-trained noncyclists and cyclists ( = 49.7 ± 5.9, 60.4 ± 4.6 ml·kg·min−1) completed a double-blind, crossover experiment after ingesting (a) 100 mg CAF, (b) 500 mg GUA (containing 130 mg CAF), or (c) placebo (P) prior to 60-min fixed cycling workload (FIX) + 15-min time trial. Oxygen uptake, heart rate, respiratory exchange ratio, blood glucose, and lactate were not different (p ≥ .052) during FIX. A significant interaction (p = .042) for perceived exertion was observed at 50-min FIX with lower rating (p = .023) for GUA versus CAF but not compared with P. Work accumulated over 15-min time trial was greater (p = .038) for GUA versus P due to higher early (1–11 min) work outputs. Work performance favored (effect size = 0.18; 95% confidence interval [0.003, 0.355], p = .046) GUA (241.4 ± 39.9 kJ) versus P (232.1 ± 46.6 kJ), but CAF (232.3 ± 43.9) was not different from GUA (effect size = 0.19; 95% confidence interval [−0.022, 0.410], p = .079) or P. Postexercise strength loss was not attenuated with GUA (−5.6 ± 8.5%) or CAF (−8.3 ± 9.4%) versus P (−10.3 ± 5.1%). Acute GUA ingestion improved work performance relative to P, but effects were trivial to small and unrelated to altered substrate oxidation or muscular strength. Ergogenicity may involve central mechanisms reducing perceived effort with GUA (containing 130 mg caffeine). Due to issues related to identical matching of dosage, whether GUA confers additional benefits beyond its CAF content cannot be determined at present.