PURPOSE: This study compared acute neuromuscular and hormonal responses and recovery in males during resistance exercises performed in Smith machine back squat (SQ) and horizontal leg press (LP). METHODS: Twelve healthy, physically active men performed SQ and LP loadings consisting of 5 sets at ten-repetition maximum. Maximal bilateral isometric force and sEMG activity of quadriceps femoris over 500 ms (MIVC) in isometric leg press, countermovement jump height, and resting twitch force were assessed before (PRE) and immediately after loadings (POST), and after recovery of 30 min (POST30), 24 h (POST24), and 48 h. Serum concentrations of cortisol (COR), growth hormone (GH), testosterone, and creatine kinase were assessed at the same time points and additionally after third set (MID). Blood lactate (BL) was measured at PRE, MID, POST, and POST30. RESULTS: Total work performed was significantly higher during SQ than LP ( 43.0 ± 5.2 kJ vs. 29.1 ± 3.1 kJ, p < 0.001). All blood-based parameters increased significantly during both loadings (p < 0.01). COR and GH were significantly higher at MID, POST, and POST30, and BL at MID during SQ than LP (p < 0.05). Neuromuscular variables decreased significantly from PRE to POST during both loadings (p < 0.05), with an interaction observed in MIVC between SQ and LP (- 10.4 vs. 6.4%, p < 0.01). All variables had returned to baseline by POST24. CONCLUSION: SQ may provide a more potent stimulus for metabolic and hormonal responses during high-volume resistance exercise, at least partly due to the greater total work performed. Nevertheless, fatigue induced within the quadriceps femoris was similar between SQ and LP.