Leap Motion Controller (LMC) is a virtual reality device that can be used in the rehabilitation of central nervous system disease (CNSD) motor impairments. This review aimed to evaluate the effect of video game-based therapy with LMC on the recovery of upper extremity (UE) motor function in patients with CNSD. A systematic review with meta-analysis was performed in PubMed Medline, Web of Science, Scopus, CINAHL, and PEDro. We included five randomized controlled trials (RCTs) of patients with CNSD in which LMC was used as experimental therapy compared to conventional therapy (CT) to restore UE motor function. Pooled effects were estimated with Cohen’s standardized mean difference (SMD) and its 95% confidence interval (95% CI). At first, in patients with stroke, LMC showed low-quality evidence of a large effect on UE mobility (SMD = 0.96; 95% CI = 0.47, 1.45). In combination with CT, LMC showed very low-quality evidence of a large effect on UE mobility (SMD = 1.34; 95% CI = 0.49, 2.19) and the UE mobility-oriented task (SMD = 1.26; 95% CI = 0.42, 2.10). Second, in patients with non-acute CNSD (cerebral palsy, multiple sclerosis, and Parkinson’s disease), LMC showed low-quality evidence of a medium effect on grip strength (GS) (SMD = 0.47; 95% CI = 0.03, 0.90) and on gross motor dexterity (GMD) (SMD = 0.73; 95% CI = 0.28, 1.17) in the most affected UE. In combination with CT, LMC showed very low-quality evidence of a high effect in the most affected UE on GMD (SMD = 0.80; 95% CI = 0.06, 1.15) and fine motor dexterity (FMD) (SMD = 0.82; 95% CI = 0.07, 1.57). In stroke, LMC improved UE mobility and UE mobility-oriented tasks, and in non-acute CNSD, LMC improved the GS and GMD of the most affected UE and FMD when it was used with CT.