This study investigated the effects of 12-SET, 18-SET, and 24-SET lower-body weekly sets on muscle strength and mass accretion. Thirty-five resistance-trained individuals (one repetition maximum [1RM] squat: body mass ratio [1RM: BM] = 2.09) were randomly divided into 12-SET: n = 13, 18-SET: n = 12, and 24-SET: n = 10. Subjects underwent an 8-week resistance-training (RT) program consisting of 2 weekly sessions. Muscle strength (1RM), repetitions to failure (RTF) at 70% of 1RM, anterior thigh muscle thickness (MT), at the medial MT (MMT) and distal MT (DMT) points, as well as the sum of both sites (ΣMT), along with region of interest for fat-free mass (ROI-FFM) were measured at baseline and post-testing. For the 1RM, there was a main time effect (p ≤ 0.0001). However, there was a strong trend toward significance (p = 0.052) for group-by-time interaction, suggesting that 18-SET increased 1RM back squat to a greater extent compared with 24-SET, (24-SET: 9.5 kg, 5.4%; 18-SET: 25.5 kg, 16.2%; 12-SET: 18.3 kg, 11.3%). For RTF, only a main time-effect (p ≤ 0.0003) was observed (24-set: 5.7 reps, 33.1%; 18-SET: 2.4 reps, 14.5%; 12-SET: 5.0 reps, 34.8%). For the MMT, DMT, ΣMT, and ROI-FFM, there was only main time-effect (p ≤ 0.0001), (MMT: 24-SET: 0.15 cm, 2.7%; 18-SET: 0.32 cm, 5.7%; 12-SET: 0.38 cm, 6.4%-DMT: 24-set: 0.39 cm, 13.1%; 18-SET: 0.28 cm, 8.9%; 12-SET: 0.34 cm, 9.7%-ΣMT: 24-set: 0.54 cm, 6.1%; 18-SET: 0.60 cm, 6.7%; 12-SET: 0.72 cm, 7.7%, and ROI-FFM: 24-set: 0.70 kg, 2.6%; 18-SET: 1.09 kg, 4.2%; 12-SET: 1.20 kg, 4.6%, respectively). Although all of the groups increased maximum strength, our results suggest that the middle dose range may optimize the gains in back squat 1RM. Our findings also support that differences in weekly set number did not impact in MT and ROI-FFM adaptations in subjects who can squat more than twice their body mass.