Unilateral and bilateral lower-body heavy resistance exercises (HREs) are used for strength training. Little research has examined whether muscle activation and testosterone (TES) responses differ between these exercises. Our purpose was to compare the effects of unilateral and bilateral lower-body HRE on muscle activity using surface electromyography (sEMG) and TES concentrations. Ten resistance-trained, college-aged male athletes (football, track and field) completed 5 testing sessions in which bilateral (back squat [BS]) and unilateral (pitcher squat [PS]) exercises were performed using a counterbalanced design. Sessions 1 and 2 determined estimated maximum strength (10 repetition maximum [10RM]) in the BS and PS. During testing session 3, muscle activation (sEMG) was measured in the right vastus lateralis, biceps femoris, gluteus maximus, and erector spinae (ES) during both BS and PS (stance leg) exercises. In sessions 4 and 5, total TES concentrations (nanomoles per liter) were measured via blood draws at baseline (preexercise), 0, 5, 10, 15, and 30 minutes postexercise after 4 sets of 10 repetitions at the 10RM. Separate repeated-measures analyses of variance examined differences in sEMG and TES between BS and PS (p < 0.05). The sEMG amplitudes were similar (p = 0.80) for BS (0.22 ± 0.06 mV) and PS (0.20 ± 0.07 mV). The TES responses were also similar (p = 0.15) between BS (21.8 ± 6.9 nmol·L(-1)) and PS (26.2 ± 10.1 nmol·L(-1)). The similar lower limb and back sEMG and TES responses may indicate that the neuromuscular and hormonal demands were comparable for both the BS and PS exercises despite the absolute work being less in the PS. The PS exercise may be an effective method for including unilateral exercise into lower-body resistance training when designing training programs for ground-based activities.