Background: Frailty is characterized by the decreased ability in older adults to handle daily or acute stressors due to age-related declines in physiological reserve and organ system performance. This condition results from the interaction of multiple physiological pathways and changes in biomarkers. Exercise programs are currently recommended to promote “healthy aging” in frail older adults. Objective: This systematic review aimed to evaluate the effectiveness of exercise program interventions in improving outcomes related to frailty, physical function, cognitive performance, and biomarkers in frail older adults. Methods: This study was designed according to the PRISMA guidelines. A systematic search was conducted in PubMed, Embase, and Scopus for studies published between 2014 and 2024. Two independent reviewers extracted data, with disagreements resolved by a third reviewer. Randomized controlled trials involving pre-frail or frail older adults aged 60 and above in all settings were included. The focus was on the impact of exercise programs, especially multicomponent interventions, on frailty outcomes and biomarkers. Results: Nine studies involving a total of 2083 participants met the inclusion criteria. The age range of participants was 65.35 ± 5.15 to 86.7 ± 4.00 years, with 64.7% being female. The results demonstrated that multicomponent exercise programs significantly improved frailty status, enhanced physical and cognitive function, and improved emotional well-being. Additionally, these programs led to significant reductions in inflammatory biomarkers, such as IL-6 and TNF-α, which are associated with frailty. Conclusion: This review highlights the beneficial effects of multicomponent exercise programs on pre-frail and frail older adults, providing evidence that these interventions improve physical and cognitive functions and emotional well-being, and reduce inflammation. These findings offer valuable insights into developing targeted interventions to manage frailty in clinical practice.