This study aimed to investigate the effects of exergames and protein supplementation on the body composition and musculoskeletal function of pre-frail older women. Methods: A randomized controlled clinical trial was conducted with 90 pre-frail older women (71.2 ± 4.5 years old) divided into five groups: control (CG); exergames training (ETG); protein supplementation (PSG); exergames combined with protein supplementation (ETPSG); exergames combined with isoenergetic supplementation (ETISG). The primary outcomes were pre-frailty status, body composition (appendicular muscle mass (ASM); appendicular muscle mass index (ASMI)) assessed by dual energy X-ray absorptiometry and gastrocnemius muscle architecture via ultrasound. Secondary outcomes were protein intake, plasma levels of interleukin (IL)-6, plantar and dorsiflexion isokinetic peak torque, and handgrip strength (HS). Data were analyzed using an ANOVA mixed model test and Bonferroni post hoc test (p < 0.05). The ETG showed a reduction of ASM (16.7 ± 3.4 vs. 16.1 ± 3.3 kg; Δ = -0.5; p = 0.02; d = 0.26) and ASMI (6.8 ± 0.9 vs. 6.5 ± 0.9 kg; Δ = -0.2; p = 0.03; d = 0.35), without changing ASM in other groups. The average protein intake in the supplemented groups (PSG and ETPSG) was 1.1 ± 0.2 g/kg/day. The dorsiflexion peak torque increased 11.4% in ETPSG (16.3 ± 2.5 vs. 18.4 ± 4.2 Nm; p = 0.021; d = -0.58). The HS increased by 13.7% in ETG (20.1 ± 7.2 vs. 23.3 ± 6.2 kg, Δ = 3.2 ± 4.9, p = 0.004, d = -0.48). The fatigue/exhaustion reduced by 100% in ETG, 75% in PSG, and 100% in ETPSG. Physical training with exergames associated with protein supplementation reversed pre-frailty status, improved the ankle dorsiflexors torque, and ameliorated fatigue/exhaustion in pre-frail older women.

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