Objective: To investigate the relationships between social isolation, health literacy, and all-cause mortality, and the modifying effect of social isolation on the latter relationship. Methods: Data were from 7731 adults aged ≥50 years participating in Wave 2 (2004/2005) of the English Longitudinal Study of Ageing. Social isolation was defined according to marital/cohabiting status and contact with children, relatives, and friends, and participation in social organizations. Scores were split at the median to indicate social isolation (yes vs. no). Health literacy was assessed as comprehension of a medicine label and classified as “high” (≥75% correct) or “low” (<75% correct). The outcome was all-cause mortality up to February 2013. Cox proportional hazards models were adjusted for sociodemographic factors, health status, health behaviors, and cognitive function. Results: Mortality rates were 30.3% versus 14.3% in the low versus high health literacy groups, and 23.5% versus 13.7% in the socially isolated versus nonisolated groups. Low health literacy (adj. HR = 1.22, 95% CI 1.02–1.45 vs. high) and social isolation (adj. HR = 1.28, 95% CI 1.10–1.50) were independently associated with increased mortality risk. The multiplicative interaction term for health literacy and social isolation was not statistically significant (p = .81). Conclusions: Low health literacy and high social isolation are risk factors for mortality. Social isolation does not modify the relationship between health literacy and mortality. Clinicians should be aware of the health risks faced by socially isolated adults and those with low health literacy.