Purpose <p>The health literacy of family caregivers (CGs) of patients with cancer is an essential factor that needs to be addressed given their vital roles in cancer care. Yet, little is known about the factors associated with the health literacy of cancer CGs, particularly during the initial stage of cancer treatment. We aimed to examine the factors associated with health literacy in CGs of patients with cancer and their impact on health-related outcomes prior to the beginning of radiation treatment.</p> Methods <p>Baseline data from an ongoing randomized controlled trial were used. The sample included CGs of patients with cancer, the majority of whom were white, non-Hispanic/Latino, spouses/partners, with incomes above $50,000 and college degrees or higher. Structural equation modeling was conducted using maximum likelihood estimation to examine the paths between demographic variables, CG health literacy, and health-related outcomes.</p> Results <p>Out of 236 CGs, one-third had limited to marginal health literacy. CGs with higher annual household income (β = .20, <i>p</i> = .009) were more likely to have higher levels of health literacy, which was associated with better overall health (β = .23, <i>p</i> = .033), lower anxiety (β = -.25, <i>p</i> = .001), and reduced fatigue (β = -.25, <i>p</i> = .011).</p> Conclusion <p>CGs with lower health literacy face greater risks of poor health, anxiety, and fatigue, which could impact their caregiving ability. Targeted interventions and practical strategies (e.g., simplified education materials, teach-back methods, health literacy screening) are needed to support CGs with limited health literacy, ensuring they have adequate resources to navigate complex cancer care. Future longitudinal studies should explore these relationships to understand long-term impacts.</p> Trial registration number <p>NCT04055948</p> Date of registration <p>08/14/2019</p>