The northeastern region of India has a high disease burden given the prevalence of chronic conditions, coupled with inadequate healthcare facilities and poor health-seeking behaviours. This region has the highest incidence of cancer in the country, in addition to the high prevalence of diabetes and hypertension. It also has the highest prevalence of tobacco and alcohol use in the country, which further contributes to an increased risk of morbidity of these conditions. In this context, health literacy and self-efficacy could potentially reduce the effects of health-risk behaviours on health outcomes. This study aims to explore the role of health literacy and self-efficacy in health-risk behaviours. A cross-sectional study was conducted with 443 adults above the age of 20 years in the city of Shillong in Meghalaya. Sixty-three per cent of the participants were females, 84.6% were college-educated and 76.3% were employed. Regression analysis indicated that being female, having higher income, education, health literacy and self-efficacy were associated with lower health-risk behaviours (R2 = 0.150, F (12, 348) = 5.131, p < 0.001). When considering the models for men and women separately, the results for men were identical to the main model but for women, self-efficacy alone negatively predicted health-risk behaviours. The model highlights gender differences in predicting health-risk behaviours. For women, having the confidence to make a behaviour change was most important despite having adequate levels of health literacy. Results thus suggest that communication and empowerment in addition to health education would be effective in reducing health-risk behaviours. Health promotion interventions should be designed to address gender- and class-specifications in the northeast region of India for improved health outcomes.