Background <p>People with limited health literacy and hypertension may lack the self-management skills needed to manage their illness, contributing to the onset and progression of important adverse health outcomes (e.g., multimorbidity). This study aimed to assess the association between health literacy and the onset and progression of hypertension-related multimorbidity among people with hypertension and whether this association is mediated by components of self-management (i.e., motivation, self-efficacy beliefs and problem-solving).</p> Methods <p>The study sample included data from 21,725 adult participants with hypertension who were followed in the Lifelines Cohort Study. Using causal mediation analysis with natural effect models, the total and direct effect of health literacy on hypertension-related multimorbidity and the indirect effects of motivation, self-efficacy beliefs and problem-solving were studied.</p> Results <p>First, after controlling for age, sex, smoking status, education level and monthly income, the total and direct effects of health literacy on the onset of hypertension-related multimorbidity were null (OR: 1.00, 95% CI: 0.99–1.01); however, an increase in problem-solving scores had an indirect effect on the onset of hypertension-related multimorbidity (OR: 0.99, 95% CI: 0.98–0.99). Second, a change from limited health literacy to adequate health literacy (OR: 0.99, 95% CI: 0.98–0.99) and an increase in motivation (OR: 0.99; 95% CI: 0.99–1.00), self-efficacy beliefs (OR: 0.99; 95% CI: 0.98–0.99) and problem-solving (OR: 0.99; 95% CI: 0.98–0.99) scores had direct and indirect effects, respectively, on the progression of hypertension-related multimorbidity.</p> Conclusions <p>A change from limited health literacy to adequate health literacy had no direct effect on the onset of hypertension-related multimorbidity but did decrease the likelihood of its progression. Problem-solving indirectly mediated only the onset; meanwhile, motivation, self-efficacy beliefs and problem-solving mediated the progression of hypertension-related multimorbidity. Improving health literacy and self-management skills can play a crucial role in preventing or delaying the onset or progression of hypertension-related multimorbidity. These improvements can significantly reduce the disease burden for individuals with limited health literacy and those living with hypertension-related multimorbidity.</p>