Information seeking is an important behavior for cancer prevention and control, but inequalities in the communication of information about the disease persist. Conceptual models have suggested that low health literacy is a barrier to information seeking, and that fatalistic beliefs about cancer may be a mediator of this relationship. Cancer fatalism can be described as deterministic thoughts about the external causes of the disease, the inability to prevent it, and the inevitability of death at diagnosis. This study aimed to examine the associations between these constructs and sociodemographic factors, and test a mediation model using the American population-representative Health Information and National Trends Survey (HINTS 4), Cycle 3 ( n = 2,657). Approximately one third (34%) of the population failed to answer 2/4 health literacy items correctly (limited health literacy). Many participants agreed with the fatalistic beliefs that it seems like everything causes cancer (66%), that one cannot do much to lower his or her chances of getting cancer (29%), and that thinking about cancer makes one automatically think about death (58%). More than half of the population had “ever” sought information about cancer (53%). In analyses adjusted for sociodemographic characteristics and family cancer history, people with limited health literacy were less likely to have ever sought cancer information (odds ratio [ OR] = 0.63; 0.42-0.95) and more frequently endorsed the belief that “there’s not much you can do . . .” ( OR = 1.61; 1.05-2.47). This fatalistic belief partially explained the relationship between health literacy and information seeking in the mediation model (14% mediation). Interventions are needed to address low health literacy and cancer fatalism to increase public interest in cancer-related information.