The limited data on childhood cancer incidence in low- and middle-income countries (LMICs), evidenced from the few cancer registries from such countries that contributed data to IICC-3 and other similar projects, makes obtaining accurate information to derive the magnitude of disparities in outcomes on a global scale, a challenge. There are, however, huge disparities in childhood cancer care outcomes globally as evidenced by survival data in high-income countries compared to low- and middle-income countries. These disparities are as a result of multifactorial, interlinked factors that are transdisciplinary and integrate basic and clinical sciences, epidemiology, social sciences, and policy. Broad social determinants have an influence on genetics and biology and affect outcomes. Several studies based on the US Surveillance, Epidemiology, and End Results data have provided evidence for racial and ethnic disparities, with Non-Hispanic Blacks and Hispanics having poorer outcomes overall, compared to Non-Hispanic Whites for both hematological and solid cancers. Single institution studies have proven that these disparities can be mitigated by patients receiving comprehensive care. Genome-wide studies have revealed the association of some genetic polymorphisms with outcomes. Socioeconomic status and the type of health insurance have been linked to racial and ethnic disparities which could have limitations on the quality of health care that is accessible, but socioeconomic status does not account for all the evident disparity. Direct and indirect costs of treatment with the attendant high rates of treatment abandonment and treatment failure are major reasons for poor outcomes in Low- and Middle-Income Countries. Geographical access, personnel, equipment, and infrastructure limitations are among several challenges faced in LMICs hampering the delivery of quality care. Access to assured quality drugs, lack of effective supportive care, unavailability of data, and childhood cancer not being prioritized in policies are major contributors to the huge disparity gap. Globally, tumor biology drives disparities in outcomes not only between the different types of cancers but also due to heterogeneity within the same cancer type. Clinical trials among cooperative groups have led to improvements in outcomes in high-income countries (HICs), but opportunities for participation of children in LMICs in clinical trials are limited. Patient, tumor, environmental factors, and policies contribute in various ways to disparities in childhood cancer outcomes.