Background: It is critical for parents of children with cancer to be knowledgeable regarding their child’s diagnosis to effectively navigate their child’s cancer care. Research investigating the role of Social Determinants of Health (SDoH) on cancer knowledge is scarce. Methods: We prospectively assessed levels of disease knowledge among parents of children with newly diagnosed cancer (past 3 months) and associations with SDoH. Our outcome measure was level of parental cancer knowledge on cancer type, stage/risk stratification, if enrolled in a therapeutic clinical trial or receiving standard of care treatment, and name of protocol if applicable (score 0-100% correct answers). Socio-demographics included parental age, sex, race/ethnicity, English proficiency, marital status, education attainment, insurance type, and employment status. Health literacy (HL) was measured using the Newest Vital Sign (NVS). Results: 182 English or Spanish-speaking parents completed surveys. 67% of participants were female (n=112) and 47% Hispanic (n=96). On average, parents answered 40% of questions correctly on the cancer knowledge survey (SD+/-19). In univariate analysis, lower cancer knowledge was associated with limited HL (p=0.003), unmarried status (p=0.015), lower education attainment [high-school or less] (p=0.048), and public insurance (p=0.006). In adjusted multivariate analysis, limited HL remained significantly associated with lower knowledge (p=0.036). Moreover, parents with limited HL were 77% less likely to know if their child was receiving treatment enrolled in a clinical trial or standard of care treatment (OR=0.13, p<0.001, 95%CI=0.065-0.403). Conclusions: Parents of children with newly diagnosed cancer scored overall low on the baseline knowledge test. Limited HL was significantly associated with lower cancer baseline knowledge after adjusting for SDoH. Our findings underscore the importance of identifying parents with limited HL to effectively increase their cancer knowledge by providing targeted education and support. Future research should assess how parental cancer knowledge affects clinical outcomes and include interventions, particularly tailored to individuals with limited HL.