Introduction: Radical mastectomy shall be a lifesaving procedure for patients with breast cancer. However, it is associated with considerable alteration of patients’ self-esteem and body image. Currently, 40% of women are subjected to breast reconstruction subsequent to radical mastectomy, ranking such surgery the most common reconstruction approach. Two-stage tissue expander-to-implant is the preferable technique that accomplished the desired aesthetic outcomes. The current study was executed to assess the safety and efficacy of Carbon-dioxide based tissue expansion, in contrast to saline-based tissue expansion. Materials and Methods: Comprehensive literature review up to 1 December 2020 was carried out throughout the following databases; PubMed, Google Scholar, Web of Science, Scopus, WHO Global Health Library, Clinical trials, Cochrane, SIGLE, NYAM, mRCT, and ICTRP to identify all clinical studies compared carbon-dioxide based and saline-based tissue expansion. Data analysis was done using Review Manager version 5.3 (RevMan5.3). The significant difference was established at P < 0.05. Results: This meta-analysis included four articles which comprised 619 reconstructed breasts. Of them, 374 breasts were reconstructed using carbon-dioxide based tissue expander, whereby 245 breasts were reconstructed using saline-based tissue expander. Carbon-dioxide based tissue expander accomplished statistically significant shorter duration to accomplish complete expansion (MD-36.28;95%CI-44.09,-28.47; P<0.001) and shorter duration to achieve complete reconstruction (MD-41.91;95%CI-54.24,-29.58; P<0.001). There was no statistically significant difference between carbon-dioxide and saline-based tissue expanders regarding the success rate (RR 1;95%CI 0.96, 1.06; P=0.85), device malfunction (RR 0.94;95%CI 0.11, 8.06; P=0.96), and implant extrusion (RR 0.71;95%CI 0.14, 3.62; P=0.68). There was no statistically significant difference between both methods regarding total; complications (RR 0.93;95%CI 0.64, 1.37; P=0.72). This includes wound infection (RR 0.46;95%CI 0.08, 2.72; P=0.39), wound dehiscence (RR 0.47;95%CI 0.10, 2.25; P=0.34), seroma (RR 1.01;95%CI 0.40, 2.57; P=0.99), and hematoma (RR 0.28;95%CI 0.06, 1.29; P=0.1). Conclusions: Carbon-dioxide based tissue expander is a safe, effective, and promising approach with considerable advancement relative to saline-based tissue expander, principally regarding the time to accomplish complete implant expansion and the time to achieve complete breast reconstruction.