Background: Palliative care plays an important role in improving the quality of life for patients with cancer and their caregivers and has been associated with increased patient satisfaction. However, palliative care knowledge in the general population is limited, and often physician referral occurs late in prognosis. The objective of this analysis was to examine factors associated with palliative care knowledge. Method: Using data from the 2018 NCI's Health Information National Trends Survey (HINTS) 5 Cycle 2, descriptive statistics, bivariate analyses, and multivariable logistic regressions were used to assess factors associated with respondents' palliative care knowledge using ORs and 95% confidence intervals as measures of association. The outcome of interest was measured with the item “How would you describe your level of knowledge about palliative care?” Possible response selections were “I've never heard of it,” “I know a little bit about palliative care,” and “I know what palliative care is and could explain it to someone else.” To reduce the risk of type 1 error, jackknife variance estimations with repeated replications were used. All analyses were conducted with the SURVEYLOGISTIC command using SAS 9.4 (SAS Institute Inc.), and the statistical significance level was set at P < 0.05. Results: A total of 3,450 respondents (weighted sample size: 249,489,772) met the inclusion criteria. About 89% (n = 3,000) of all respondents had inadequate knowledge of palliative care. Multivariable analyses indicated that frequent health care utilization as defined as ≥ 2 times per year [OR, 3.01; 95% confidence interval (CI), 2.65–3.58], female gender (OR, 2.15; 95% CI, 1.31–3.59), being married (OR, 2.02; 95% CI, 1.14–3.59), having a college degree or higher (OR, 13.83; 95% CI, 1.71–12.04), and having a regular source of care (OR, 2.67; 95% CI, 1.37–1.90) had greater odds of adequate palliative care knowledge. Those without a cancer diagnosis were less likely to have adequate knowledge of palliative care (OR, 0.49; 95% CI, 0.41–0.89). Conclusions: Knowledge of palliative care in the United States is low, particularly for those not already actively using their available healthcare system. Public health education efforts are needed to target subgroups of the U.S. population identified by this analysis to increase palliative care knowledge. Impact: Healthcare providers have a major role to play in improving palliative care knowledge.