Virtual reality (VR) has emerged as a powerful option for rehabilitation by providing real-time performance feedback and a safe and customized training environment. This study aimed: (1) to investigate the association between presence in the virtual environment, usability of the system, intrinsic motivation, and immersion in VR gaming designed for rehabilitation after musculoskeletal injury; and (2) to examine the users’ emotional response in terms of pleasure, arousal, and dominance after participating in VR gaming. Thirty-seven individuals aged 23.69 ± 6.98 years participated in five customized VR games designed to provide a complete rehabilitation session after a musculoskeletal injury. Pearson product-moment correlation coefficients and multiple regression analyses were used to investigate the relationship between presence in virtual environments and immersive tendencies, the usability of the system, and intrinsic motivation. The Wilcoxon Signed Rank Test was conducted to evaluate the impact of participation in VR gaming on participants’ presence in virtual environments. Significant correlations were found between presence and immersive tendencies (r = −.40, p = .017), intrinsic motivation (r = .42, p = .013), and usability of the system (r = .64, p < .001). The linear regression model explained 59% of the total variance in the presence of virtual environments. There was a statistically significant increase in the pleasure scores from the beginning to the end of the session. Our results indicate that VR may be useful in increasing adherence to treatment to recover from musculoskeletal injuries.