The growing burden of non-communicable diseases (NCDs) in low- and middle-income countries may have implications for health system performance in the area of financial risk protection, as measured by catastrophic health expenditure (CHE). We compare NCD CHE to the CHE cases caused by communicable diseases across health systems to examine whether: 1) disease burden and CHE are linked, 2) NCD CHE disproportionately affects wealthier households, and 3) whether the drivers of NCD CHE differ from the drivers of communicable disease CHE. We used the Study on Global Aging and Adult Health survey, which captured nationally representative samples of 44,089 adults in China, Ghana, India, Mexico, Russia, and South Africa. Using two-part regression and random forests, we estimated out-of-pocket spending and CHE by disease area. We compare the NCD share of CHE to the NCD share of disability-adjusted life years (DALYs), or years of life lost to disability and death. We tested for differences between NCDs and communicable diseases in the out-of-pocket costs per visit and the number of visits occurring before spending crosses the CHE threshold. NCD CHE increased with the NCD share of DALYs except in South Africa, where NCDs caused more than 50% of CHE cases but only 19% of DALYs. A larger share of households incurred CHE due to NCDs in the lowest than the highest wealth quintile. NCD CHE cases were more likely to be caused by five or more health care visits relative to communicable disease CHE cases in Ghana (p = 0.003), India (p = 0.004), and China (p = 0.093). Health system attributes play a key mediating factor in how disease burden translates into financial risk protection by disease. Health systems must target the specific characteristics of CHE by disease area to bolster financial risk protection as the epidemiological transition proceeds.