Background <p>This study investigated the differential effects of single-set (SS) and multiple-set (MS) resistance training on muscle strength, hypertrophy, and neuromuscular performance in sedentary young men. Understanding how training volume influences early adaptations is essential for optimizing resistance training prescriptions in untrained populations.</p> Methods <p>Thirty-four sedentary males were randomly assigned to SS (<i>n</i> = 12), MS (<i>n</i> = 11), or control (CG, <i>n</i> = 11). The training groups completed an eight-week resistance training program performed twice per week, consisting of seven exercises with a maximum of ten repetitions each. The SS group performed one set per exercise, whereas the MS group performed three sets. Pre- and post-intervention assessments included anthropometry (body fat, lean mass, limb circumferences) and neuromuscular tests: handgrip strength, vertical jump, 20-m sprint, Yo-Yo IR-1, medicine-ball throws, and one-repetition maximum (1-RM) bench press and squat.</p> Results <p>The MS protocol induced greater hypertrophic adaptations (right and left leg muscle cross-sectional area: +11.3%) compared with SS (~ 6–8%) and CG. Strength gains were also superior in MS for bench press (+ 19.8%) and squat (+ 14.8%). Improvements in vertical jump (+ 6.4%) and Yo-Yo IR1 performance (+ 3.2%) were more pronounced in MS, while SS produced moderate but significant gains across most performance outcomes.</p> Conclusions <p>Both SS and MS resistance training improved strength, power, and morphological characteristics after eight weeks; however, the multiple-set protocol produced more robust hypertrophic and neuromuscular adaptations. These findings reinforce the presence of a volume-dependent dose–response relationship in the initial phases of resistance training for untrained individuals.</p> Trial registration <p>ClinicalTrials.gov NCT07337304. Registered on 14 December 2025. Retrospectively registered.</p>