Caffeine and beta-alanine are widely used in multi-ingredient pre-workout supplements believed to enhance resistance training, but their specific role in driving this effect remains unclear. The current study employed a randomized, triple-blinded, placebo-controlled and crossover experimental design to explore the acute effects of caffeine (200 mg), beta-alanine (3 g), or their combination (200 mg caffeine and 3 g beta-alanine; C+B-A) administered 30 min prior to resistance training (RT) on mechanical, physiological, and perceptual variables. Twenty-one young resistance-trained males (age = 23.5 ± 4.5 years, body mass = 82.1 ± 10.2 kg) visited the laboratory on six occasions: one familiarization session, one preliminary testing session for load determination, and four experimental sessions which differed only in supplementation condition and involved four supersets of bench press and bench pull exercises. The supplement condition did not significantly affect any mechanical variables (p ≥ 0.335), except for the velocity of the last repetition of the set, where beta-alanine produced lower values (0.383 m/s) compared to placebo (0.407 m/s; p < 0.05), with no differences observed for C+B-A (0.397 m/s) and caffeine (0.392 m/s). Heart rate was consistent across the different supplement conditions with the exception of the higher values observed immediately before the start of the RT session for placebo compared to caffeine (p = 0.010) and C+B-A (p = 0.019). Post-RT blood lactate concentration (p = 0.384), general and local ratings of perceived exertion (p = 0.177 and 0.160, respectively), and readiness (p = 0.281-0.925), did not differ significantly between supplement conditions. Selected supplements have minimal effects on performance and physiological responses in agonist-antagonist upper-body superset RT not leading to failure.