Background: Social determinants of health (SDoH) encompass the various environmental conditions that influence health, well-being, outcomes, and potential risks. Adverse SDoH can exacerbate health disparities and result in a reduced health-related quality of life (HRQoL). We conducted an investigation into the impact of SDoH on the HRQoL of cancer survivors. Methods: The study population was a nationally representative cohort of individuals aged 20-80 years who took part in the United States National Health and Nutrition Examination Survey (NHANES) 2001 to 2018 cycles. We evaluated HRQoL by measuring the number of physically unhealthy days, mentally unhealthy days, inactive days, as well as assessing social support and emotional well-being. We used logistic regression models to investigate the impact of each SDoH on the HRQoL of cancer survivors. Results: We included 4,780 participants in our analyses, comprising 2,533 women and 2,247 men. The participants mean age was 66 (±14) years at the time of enrollment, and 55 (±17) years at the time of cancer diagnosis. Among the total study population, non-melanoma skin cancer (16%) was the most prevalent cancer type. After adjusting for age, age at cancer diagnosis and gender, people who had the lowest self-reported health were more likely to have completed fewer years of education (OR 0.380 [95% CI: 0.32 - 0.45], p < 0.0001), be unemployed (OR 2.30 [1.91 - 2.77], p < 0.0001), have lower family income (OR 0.36 [0.28 - 0.45], p < 0.0001), be food insecure (OR 3.90 [2.80 - 5.44], p < 0.0001), not have private health insurance (OR 1.68 [1.37 - 2.07], p < 0.0001), and have been hospitalized overnight in the last year (OR 5.23 [3.49 - 7.83], p < 0.001) compared to those with the highest self-reported health. SDoH including employment status, family income, food security status, health insurance type, and overnight hospital patient status, were significantly associated with physical and mental health, and physically active days. Level of education and food security were significantly associated with social support and emotional well-being. Conclusions: Adverse SDoH were associated with the reduced HRQoL of cancer survivors in the United States. These findings underscore the importance of addressing and mitigating these social determinants in order to alleviate health disparities and improve the overall well-being and quality of life for cancer survivors.