Effective interventions for indicated fall prevention are necessary for older adults with frailty. We aimed to determine the effectiveness of a Multi-system Physical Exercise (MPE) for fall prevention and Health-Related Quality of Life (HRQOL) in pre-frail older adults. This randomized control trial with allocation concealment included 72 adults aged 65 and above, identified as pre-frailty and with mild and moderate fall risk scores measured by the Physiological Profile Assessment (PPA). Randomly, using block randomization, participants were divided into two groups: an MPE group (n = 36) and a control group (n = 36). The intervention consisted mainly of proprioception, muscle strengthening, reaction time, and balance training and was carried out three days per week for 12 weeks. The primary outcome was fall risk assessed using PPA at 12 weeks post-baseline and at a 24 week follow-up. Significant differences were found in the improvement in fall risk, proprioception, muscle strength, reaction time and postural sway, and fear of fall scores in the MPE group compared with controls at week 12 and 24. In addition, HRQOL had increased significantly in the MPE group in comparison to controls. The MPE program significantly increased muscle strength and improved proprioception, reaction time, and postural sway leading to fall risk reduction in older adults with pre-frailty. Therefore, the MPE program is recommended for used in day-to-day primary care practice in the pre-frail population.