Chronic diseases are the leading causes of morbidity and mortality and account for approximately 60% of all deaths worldwide. Self-management is a key strategy to manage chronic diseases, and there is emerging evidence recommending targeting both health literacy (HL) and patient activation (PA) to improve chronic disease self-management outcomes. The aim of this systematic review is to summarise the current evidence on the impact of HL- and PA-led interventions on self-management outcomes using randomised control trials (RCTs). Six well known databases (MEDLINE, Web of Science, Scopus, Science Citation Index, EMBASE and Academic Search Complete) were searched for RCTs of chronic disease self-management interventions targeting both HL and PA and published between 2004 and June 2021. The search terms included chronic disease, self-management, patient activation/engagement and health literacy/education. Ten studies were eligible for inclusion. We found that patients with low HL and PA levels are most likely to benefit from the interventions. The moderate improvements in PA and HL in the reviewed studies were translated into some improvements in physical activity and mental health outcomes but failed to improve patients' quality of life and healthcare utilisation outcomes. Patients with low HL were more likely to have higher PA levels after the interventions. This review suggests that both HL and PA are essential pillars for improving chronic disease self-management outcomes. However, more studies are needed to explore the long-term impacts of a combination of HL and PA on chronic disease self-management outcomes.