Background: Frailty is a multifactorial geriatric syndrome characterized by progressive decline in health and associated with decreased muscle mass, strength, and functional capacity. Resistance training (RT) combined with protein or amino acids supplementation has been shown to be promising for mitigating age-related impairments. Aim: To investigate the chronic effects of different strategies of protein and derivatives supplementation in association with RT on selected health-related parameters in pre-frail and frail elderly. Methods: This is a series of double-blind, randomized, placebo-controlled, parallel-group clinical trials. Volunteers will be divided into nine groups, comprising four different sub-studies evaluating the effects of: isolated leucine supplementation (study 1); protein source (whey vs. soy – study 2); combination of whey protein and creatine (study 3); and sexual dimorphism on the response to protein intake and RT (males vs. females – study 4). Muscle cross-sectional area, fiber cross-sectional area, body composition, lower-limb maximal dynamic and isometric strength, functionality, lipid profile, biochemical parameters, renal function, quality of life, and nutritional status will be assessed before and after a 16-week intervention period. Data will be tested for normality and a mixed-model for repeated measures will be conducted to assess within- and between-group effects of the intervention on the dependent variables. Confidence intervals (95%), effect sizes, and relative changes will also be determined, with significance set at p < 0.05.