ABSTRACT Background Tissue plasminogen activator (tPA) is a common therapeutic agent approved to treat patients with stroke. When the agent is administered within 4.5 hours of stroke onset, tPA administration helps to restore blood flow to brain regions affected by a stroke, thereby limiting the risk of damage and functional impairment. However, research evaluating the use of tPA on aphasia – loss of the ability to understand or express speech – a common post-stroke condition is limited. A meta-analysis of available evidence was performed to assess the association between the use of tPA on aphasia post-stroke. Methods A literature search was performed using the PubMed, Web of Science, and SCOPUS electronic database using keywords “tPA”, “tissue plasminogen activator”, “aphasia”, and “stroke” published in English since 2010. An initial search revealed 7, 069, 6,682, and 289 studies in PubMed, Web of Science, and SCOPUS, respectively. Studies without a measure of aphasia impairment in adults as well as case studies and reviews were excluded. After quality assessment and a review of study abstracts, 14 relevant studies were identified for full text review. Among the 14, ten were deemed appropriate for inclusion and feature extraction. Results Associations between tPA and aphasia outcomes in each of the included studies were translated to odds ratios (ORs) and study features were coded for inclusion in a random effects meta regression. Results revealed a statistically significantly higher likelihood of improvement in the level of post-stroke aphasia among those receiving tPA compared with those not receiving tPA (odds ratio [OR], 2.1963, CI = 0.5994, 3.7932). Model statistics did however indicate substantial heterogeneity (I2 = 96.94%, Ƭ2 = 32.65) between studies. After removal of two outliers from the analysis set, the estimates improved substantially (OR = 1.8643, CI = 1.2131, 2.5155), and heterogeneity was reduced (I2 = 76.28%, Ƭ2 = 4.22). Estimates were robust to the inclusion of study location, metric used to measure aphasia, observed recovery duration, and size of the sample. Conclusion This meta-analysis found an increased likelihood of aphasia recovery in patients receiving tPA following stroke and significant improvement in communication from tPA receipt. However, further prospective studies with greater sample heterogeneity are needed to determine the appropriate window for tPA use, the duration of improvement, and the long-term effects on communication outcomes.