Introduction: While high-income countries report survival rates exceeding 90% for children and adolescents with acute B-cell lymphoblastic leukemia (B-ALL), low- and middle-income countries continue to experience higher mortality rates, influenced by delays in diagnosis, limitations in supportive care, and challenges in adapting therapeutic protocols. Real-world evidence on the impact of different treatment protocols in resource-limited settings remains scarce. Objectives: To compare overall survival during treatment of B-ALL in children and adolescents treated with different therapeutic protocols (BFM and GBTLI) in a resource-limited setting. Methods: We conducted a retrospective cohort analysis of patients aged 0 to 19 years diagnosed with B-ALL and registered between 2007 and 2022 at a philanthropic High-Complexity Oncology Care Center in Salvador, Bahia, Brazil. Survival outcomes were estimated using the Kaplan–Meier method and compared between the BFM (Berlin–Frankfurt–Münster) and GBTLI (Brazilian Cooperative Group for the Treatment of Childhood Acute Lymphoblastic Leukemia) treatment protocols using log-rank tests. To assess risk factors for mortality, a multivariable Cox proportional hazards regression analysis was performed. A p-value < 0.05 was considered statistically significant. Findings: A total of 127 patients were from the state of Bahia. The mean age was 8.1 years; 88.98% were Black or Brown race, 57.47% belonged to families with a monthly income equal to or below one minimum wage, 60.63% were underweight at diagnosis, and 63.87% were classified as high risk for relapse. There were 37 deaths, primarily due to sepsis. The five-year overall survival rate was 71%. Patients treated with the GBTLI protocol had a higher survival rate (79.4%) compared with those treated with the BFM protocol (53.5%) (p = 0.002). Survival rates were 70.9% among Black patients and 71.4% among White patients. The BFM protocol was associated with a higher risk of death compared with the GBTLI protocol (hazard ratio [HR] 4.50; 95% confidence interval [CI] 1.86–10.87). Conclusions/Implications: The findings indicate that intensive treatment protocols, such as BFM, require adaptation in low- and middle-income countries, as patients with significant socioeconomic vulnerability and those treated in centers with limited human and material resources may not tolerate intensive therapy, compromising treatment effectiveness and increasing mortality rates. In resource-limited settings, optimizing outcomes in pediatric B-ALL requires timely diagnosis, risk- and context-adapted protocols, strengthened supportive care, and continuous outcome monitoring. The adoption of less intensive protocols, such as GBTLI or similar approaches, is recommended in regions such as northeastern Brazil or other low- and middle-income countries, given the higher survival rates associated with these protocols in such contexts.