Background Data: Degenerative lumbar spine, including spondylolisthesis, is a common clinical condition that affects humans in the most productive period of their life. There are many surgical options for the management of such conditions after the failure of conservative therapy. Recently, there has been a great debate regarding the use of minimally invasive (MI) versus open transforaminal lumbar interbody fusion (O-TLIF) in the treatment of single-level low-grade lumbar spondylolisthesis, so there was a need to reach a consensus over this issue. Purpose: To compare the clinical efficacy and safety of MI-TLIF versus O-TLIF in the treatment of single-level low-grade degenerative lumbar spondylolisthesis. Study Design: A systematic review for recent studies in the context and meta-analysis. Patients and Methods: We searched online databases of PubMed, Google Scholar, Cochrane Library, and DOAJ (2016–2020), and the search yielded 1352 articles. Based on our inclusion and exclusion criteria, we included retrospective, prospective, and randomized control trials, which came down to 11 research articles. Operative time, blood loss, hospital stay, back pain scores (Visual Analogue Scale), functional score (Oswestry Disability Index), complication rate, and reoperation rate for both techniques were recorded and presented as means. We then performed a meta-analysis. Results: There is an overall advantage for the MI-TLIF over the O-TLIF in different parameters. There was a statistically significant difference in blood loss of −0.954 ml (p = 0.000) and hospital stay of −1.19 days (P = 0.000), favoring M-TLIF. There was a statistically insignificant difference in the total operative time (P = 0.071), the postoperative VAS of −0.22 (P = 0.384), and the postoperative ODI of −2 (P = 0.331). Moreover, there was a reduced combined odds ratio for complications and a reduced odds ratio for re-operation. Conclusion: The reported data in this study suggest that there was a significant difference in operative blood loss and hospital stay between both groups that favor the MI-TLIF procedure. In contrast, there was no significant difference in operative time, VAS, ODI, reoperation rate, and rate of postoperative complications between both groups. (2021ESJ235)