Introduction: Minocycline administration has demonstrated encouraging multi-target anti-neuroinflammatory effects with potential benefits in acute ischemic stroke in small studies. Previous meta-analyses also reported positive clinical outcomes with minocycline use. Recently, the EMPHASIS Trial, a large-scale, multi-center, double-blind RCT was published. The addition of this highly powered RCT requires re-evaluation of the available evidence. This meta-analysis focuses on the neuroprotective efficacy of minocycline administration in patients with acute ischemic stroke. Methods: A total of 504 articles were retrieved from Medline via PubMed, Embase, Scopus, and Web of Science. Eight studies met the inclusion criteria and were included in the analysis. The National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) were the primary outcomes. Secondary outcomes included safety endpoints; stroke recurrence and mortality. Meta-analysis was performed using R Software (V4.5.0). Random effects model with 95% Confidence Interval was used. Heterogeneity was assessed using the I2 statistics. Results: Eight studies met the eligibility criteria encompassing 2293 patients with AIS (Minocycline n = 1149, Placebo or Standard Care n = 1144). Seven studies were included in NIHSS analysis ( Minocycline — 1080, Control — 1074). The meta-analysis showed statistically significant reduction in NIHSS ( MD; – 1.92, 95% CI; – 0.68 - – 3.16, p = 0.0024) with substantial heterogeneity (I2 = 93.5%). Sensitivity analysis revealed that Lampl et al contributed significantly towards heterogeneity. The association remained significant after omission of this study ( MD = –1.1188, 95% CI; – 0.4151 - – 1.8225, p = 0.0018, I2 = 59.9%). Three studies reported BI (Minocycline n = 117, Control n = 69). The pooled mean difference favored minocycline (MD = 8.22, 95%CI; – 0.45 - 16.88, I2 = 71.5%) though analysis was not statistically significant (p = 0.0632) . Minocycline administration also yielded favorable results in mRS reported in two studies ( MD = -0.89, 95% CI; −0.25 - −1.54, p = 0.0065, I2 = 76.4%) although small sample size ( Minocycline n = 97, Control n = 104) warrants cautious consideration. Three studies reported stroke recurrence (Minocycline n = 1005, Control n = 1009) with no statistically significant difference observed between two groups ( OR = 1.03, 95% CI; 0.70 - 1.50, p = 0.8921). Mortality reported in two studies only ( Minocycline n = 931, Control n = 932) favored minocycline ( OR = 0.75, 95% CI; 0.39 - 1.46, p = 0.4040, I2 = 0.0%) though limited sample size compromises the reliability of this finding . Conclusion: Minocycline administration demonstrates clinically meaningful and potentially beneficial neuroprotective effects with fewer adverse events. However, the validity of results is limited by the small sample size of available studies. Our results underscore the need for large robust randomized controlled trials to establish definitive conclusions. Until then, minocycline administration should be considered cautiously on a patient by patient basis.