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Short set configurations attenuate cardiovascular responses, reduce perceived exertion and allow for greater mechanical performance compared with longer sets. Mid-term to long-term adaptations to resistance training across set configurations remain unexplored in postmenopausal women. This study will explore cardiovascular, metabolic, neuromuscular and perceptual adaptations to 12-week resistance training programmes differing in set configuration. Forty physically active postmenopausal women will participate. After medical screening, they will complete four pretest assessments measuring cardiovascular, metabolic, neuromuscular and body composition variables. Participants will then be randomly assigned to a control group or one of two experimental groups. Each session, experimental groups will complete 36 repetitions per exercise (leg press, bench press, leg curl and lat pull-down) with a 12-repetition maximum load. The 4S group will complete nine sets of 4 reps with 45 s of rest, while the 9S group will do four sets of 9 reps with 120 s of rest. The intervention will span 12 weeks with 24 training sessions. Afterwards, all participants will repeat the initial assessments. Experimental groups will return 3 months later for follow-up evaluations of cardiovascular, metabolic and body composition outcomes. A 3×3 repeated-measures analysis of variance will be used to analyse the effects of set configuration (4S, 9S, control) over time (pretest, post-test, follow-up). The study was approved by the Galician Regional Government Ethical Committee. All participants will receive detailed oral and written information before providing informed consent. Results will be widely disseminated, including through outreach events to promote knowledge transfer. Trial registration number: NCT05544357; registration date: 7 December 2022.