Hematopoietic stem cell transplantation (HSCT) is a potentially curative option for adults with acute lymphoblastic leukemia (ALL) who have achieved remission. This systematic review and meta-analysis compare the efficacy of total body irradiation (TBI) versus chemotherapy (CHT) based regimens for conditioning in adult ALL patients being prepared for HSCT. A comprehensive literature search was conducted in MEDLINE, Embase, the Cochrane Library, and relevant trial registries from their inception to August 2024. The inclusion criteria encompassed all randomized controlled trials (RCTs) and cohort studies that compared TBI with CHT as conditioning regimens prior to HSCT in adult patients with ALL. The primary outcomes assessed were overall survival (OS) and event-free survival (EFS). All statistical analyses were carried out using RevMan version 5.4, using a random-effects model. This meta-analysis includes 20 cohort studies and one RCT. The relative risk (RR) for OS was 1.37 (95% CI: 1.20-1.57), while the RR for EFS was 1.28 (95% CI: 1.15-1.43), highlighting the superior efficacy of TBI-based regimens in this patient population. TBI was also superior in terms of relapse rate (RR 0.71). The 2 regimens were comparable in terms of nonrelapse mortality, acute graft-versus-host disease (GVHD), and chronic GVHD. When used for conditioning prior to HSCT, TBI-based conditioning regimens demonstrate superior OS, EFS, and relapse outcomes compared to CHT-based regimens.