AimsTo summarize the effects of semaglutide 2.4 mg on weight‐related quality of life (WRQOL) and health‐related quality of life (HRQOL), focusing on the confirmatory secondary endpoint of physical functioning.Materials and MethodsThe STEP 1–4 Phase 3a, 68‐week, double‐blind, randomized controlled trials assessed the efficacy and safety of semaglutide 2.4 mg versus placebo in individuals with overweight/obesity. WRQOL and HRQOL were assessed by change from baseline to Week 68 in two different but complementary measures, the Impact of Weight on Quality of Life‐Lite Clinical Trials Version (IWQOL‐Lite‐CT; STEP 1 and 2) and the SF‐36v2 Health Survey Acute (SF‐36v2; STEP 1–4).ResultsSuperiority for semaglutide 2.4 mg over placebo based on IWQOL‐Lite‐CT and SF‐36v2 physical functioning scores was confirmed in STEP 1 and 2 and in STEP 1, 2 and 4, respectively. At Week 68, a greater proportion of participants treated with semaglutide 2.4 mg than with placebo reached meaningful within‐person change (MWPC) thresholds for IWQOL‐Lite‐CT Physical Function scores in STEP 1 (51.8% vs. 28.3%; p < 0.0001) and STEP 2 (39.6% vs. 29.5%; p = 0.0083) and the MWPC threshold for SF‐36v2 Physical Functioning in STEP 1 (39.8% vs. 24.1%; p < 0.0001), STEP 2 (41.0% vs. 27.3%; p = 0.0001) and STEP 4 (18.0% vs. 6.6%; p < 0.0001). All other IWQOL‐Lite‐CT and SF‐36v2 scale scores in STEP 1–4 were numerically improved with semaglutide 2.4 mg versus placebo, except for SF‐36v2 Role Emotional in STEP 2.ConclusionsSemaglutide 2.4 mg significantly improved physical functioning, with greater proportions of participants achieving MWPC compared with placebo, and showed beneficial effects on WRQOL and HRQOL beyond physical functioning.