Males have higher tuberculosis incidence and mortality rates than females. This study aimed to assess how sex differences in tuberculosis incidence and mortality could be explained by sex differences in HIV, antiretroviral treatment (ART) uptake, smoking, alcohol abuse, undernutrition, diabetes, social contact rates, health-seeking patterns, and treatment discontinuation. We developed an age-sex-stratified dynamic tuberculosis transmission model and calibrated it to South African data. We estimated male-to-female (M:F) tuberculosis incidence and mortality ratios, the effect of the abovementioned factors on the M:F ratios and PAFs for the tuberculosis risk factors. Over the period 1990–2019, the M:F ratios for tuberculosis incidence and mortality rates persisted above 1.0, and the figures reached 1.70 and 1.65, respectively, by the end of 2019. In 2019, HIV contributed greater increases in tuberculosis incidence among females than males (54.5% vs. 45.6%); however, females experienced more reductions due to ART than males (38.3% vs. 17.5%). PAFs for tuberculosis incidence due to alcohol abuse, smoking, and undernutrition, in men were 51.4%, 29.5%, and 16.1%, respectively, higher than females (30.1%, 15.4%, and 10.7%, respectively); the PAF due to diabetes was higher in females than males (22.9% vs. 17.5%). Lower health-seeking rates in males accounted for a 7% higher mortality rate in men. The higher burden of tuberculosis in men highlights the need to improve men’s access to routine screening and ensure earlier diagnosis. Sustained efforts in providing ART remain critical in reducing HIV-associated tuberculosis. Additional interventions to reduce alcohol abuse and tobacco smoking are also needed.