Background: Hematopoietic stem cell transplant (HSCT) is indicated in pediatric acute lymphoblastic leukemia (ALL) patients who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning have been employed before HSCT: total body irradiation (TBI) based regimens and chemotherapy alone (CHT). The use of TBI is favorable in adults with ALL, and it has also demonstrated excellent efficacy in the pediatric population. However, the lifelong adverse events of TBI are a substantial concern in younger patients. This study compares the efficacy and safety of TBI and CHT conditioning in pediatric, adolescent and young adult ALL patients (0-24 years old). Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane, and Clinicaltrials.gov from inception to November 25, 2021, using MeSH terms and keywords for ‘acute lymphoblastic leukemia’, ‘whole body irradiation’, ‘child’, ‘adolescent’ and ‘young adult’. Efficacy outcomes considered were overall survival (OS), event-free survival (EFS), and relapse. Safety outcomes were acute (a) and chronic (c) graft-versus-host disease (GVHD), and non-relapse mortality/transplant-related mortality (NRM/TRM). Estimates of risk ratios (RR) for dichotomous variables and hazard ratios (HR) for OS and EFS were pooled using a random-effects model in Revman v5.4. Results: The initial search revealed 1544 articles. After excluding reviews, duplicates, and non-relevant articles, we included data from 16 studies (2 randomized controlled trials, 1 non-randomized prospective study and 13 retrospective studies). TBI based and CHT conditioning were evaluated in 4656 and 1500 patients, respectively. The most common TBI and CHT regimens were TBI + cyclophosphamide (Cy) + etoposide (3 studies) and busulfan + Cy (6 studies), respectively. The TBI dose utilised ranged from 8-12 Gy, with 12 Gy being the most common (8 studies). The median age ranged from 4 months to 13.3 years; and the median follow up was 1.2-9.7 years. In comparison with TBI conditioning, CHT alone was associated with significantly worse OS (HR 1.61, 95% CI 1.06-2.44; p = 0.03; I2 = 79%), EFS (HR 2.01, 95% CI 1.26-3.20; p = 0.003; I2 = 60%) and risk of relapse (RR 1.44, 95% CI 1.23-1.68; p = 0.00001; I2 = 37%). There was reduced risk of aGVHD with CHT (RR 0.79, 95% CI 0.66-0.93; p = 0.006; I2 = 51%), but the difference was not significant when only grade 3-4 aGVHD was considered (RR 1.01, 95% CI 0.80-1.27; p = 0.95; I2 = 0%). The two regimens were comparable in terms of risk of cGVHD (RR 0.87, 95%CI 0.64-1.18; p = 0.38; I2 = 43%) and NRM/TRM (RR 1.24, 95% CI 0.99-1.55; p = 0.06; I2 = 66.8%). Conclusions: In pediatric and young adult ALL patients undergoing HSCT, TBI conditioning has better efficacy and similar safety compared to CHT alone.