This systemic review and meta-analysis aimed to investigate the burden of tuberculosis immune reconstitution syndrome (TB-IRIS) and associated mortality to highlight the importance of future direction in preventing and treatment of TB-IRIS. Randomized clinical trials (RCTs) that compared early antiretroviral therapy (ART) versus late ART were included. PubMed, EMBASE, Science Direct and Cochrane Central Register of Controlled Trials electronic databases were searched. This meta-analysis included 8 RCTs with a total of 4, 425 participants. The result of analysis showed that early initiation of ART was associated with increase in TB-IRIS (RR = 1.83; 95% CI: 1.24-2.70,  = 0.002; I = 74%,  = 0.0007) and TB-IRIS associated mortality (RR = 6.05; 95% CI: 1.06-34.59,  = 0.04; I = 0%,  = 0.78). Early ART was associated with overall mortality compared with late ART initiation. Grade 3 or 4 adverse events, achieving lower viral load and development of new AIDS-defining illness were not associated with the time of ART initiation. Early ART in HIV/TB co-infected patients resulted conclusive evidence of increased TB-IRIS incidence and TB-IRIS associated mortality. Hence, the finding calls for clinical judgment as to the benefits of initiating ART earlier against the risk of TB-IRIS and associated mortality.