Background: There is conflicting evidence as to whether intra-arterial thrombolysis (IAT) adds benefit in patients with acute stroke who undergo mechanical thrombectomy (MT). Methods: We conducted a systematic review to identify studies that evaluate IAT in patients with acute stroke who undergo MT. Data were extracted from relevant studies found through a search of PubMed, Scopus, and Web of Science until February 2023. Statistical pooling with random effects meta-analysis was undertaken to evaluate odds of functional independence, mortality, and near-complete or complete angiographic recanalization with IAT compared to no IAT. Results: A total of 18 studies were included (3 matched, 14 unmatched, and 1 randomized). The odds ratio (OR) for functional independence (modified Rankin Scale: 0–2) at 90 days was 1.14 (95% confidence interval (CI): 0.95–1.37, p = 0.17, 16 studies involving 7572 patients) with IAT with moderate between-study heterogeneity (I² = 38.1%). The OR for functional independence with IAT was 1.28 (95% CI: 0.92–1.78, p = 0.15) in studies that were either matched or randomized and 1.24 (95% CI: 0.97–1.58, p = 0.08) in studies with the highest quality score. IAT was associated with higher odds of near-complete or complete angiographic recanalization (OR: 1.65, 95% CI: 1.03–2.65, p = 0.04) in studies that were either matched or of randomized comparisons. Conclusion: Although the odds of functional independence appeared to be higher with IAT and MT compared with MT alone, none of the results were statistically significant. A prominent effect of the design and quality of the studies was observed on the association between IAT and functional independence at 90 days.