Interventions targeting social cognition following moderate-to-severe Traumatic Brain Injury (TBI) have shown some benefit, however, there remains a need to systematically review, statistically synthesize, and evaluate these interventions to inform the development of Clinical Practice Guidelines. Six databases were searched from inception to May 2024. Eligible studies targeted adults with a moderate-to-severe TBI (P); evaluated interventions targeting social cognition (I); compared to a control, baseline performance, or phase without treatment (C); based on objective social-cognitive ability/performance (O). Studies were screened by two independent reviewers. A random effects model estimated treatment effects for RCTs (Hedge’s g) and observational (pre–post) studies (SMD) separately. Risk of bias was assessed. Certainty of evidence was evaluated using GRADE. Twenty-five studies were eligible, including 478 participants. RCTs targeting emotion perception and ToM produced a small effect (g = 0.38 (95%CI, 0.17, 0.59), p < .001). Observational studies targeting emotion perception and ToM produced a small-medium effect (SMD = 0.42 (95% CI 0.22, 0.61), p < .001). Interventions targeting empathy or alexithymia were limited. Our review provides initial evidence for the effectiveness of social-cognitive interventions targeting emotion perception and/or ToM. More research is needed to develop and evaluate interventions for other social-cognitive domains, including empathy and alexithymia.