This paper estimated the relationship between employment and depression, hypertension, diabetes and tuberculosis in South Africa between 2008 and 2014. South Africa has high levels of economic inactivity and unemployment as well as a high disease burden occasioned by depression, other non-communicable diseases and tuberculosis. Data came from the National Income Dynamics Study panel dataset. Using fixed effects, random effects and pooled ordinary least squares regressions, depression and diabetes were associated with a 4–6 percentage point decline in employment probability, while tuberculosis was associated with a 12–13 percentage point employment decline. The results suggested that the employment-health relationship possibly operated through illness being associated with increased economic inactivity, rather than through making the search efforts of the unemployed unsuccessful. Moreover, the employment-health relationship not only existed contemporaneously, but extended into the future (especially for the physical health indicators).