E-cigarettes are often marketed as a safer alternative to combustible cigarettes. However, their health effects, especially those associated with long-term use, remain largely uncertain. We conducted an umbrella review of the cardiopulmonary and carcinogenic risks of e-cigarette use, distinguishing between short-term and long-term health effects. The search for systematic reviews was conducted across four electronic databases through 25 January 2022. Methodological quality was assessed using the AMSTAR-2 quality appraisal tool. Seventeen systematic reviews, including five meta-analyses, were included in our umbrella review. There was a clear underreporting of e-cigarette devices and e-liquid types, e-cigarette and cigarette exposure, and the health and smoking status of study participants. Overall, the findings suggest that short-term use of e-cigarettes may be associated with acute cardiopulmonary risks, although to a lesser extent than cigarette use. Long-term e-cigarette use may have pulmonary/respiratory benefits in those who switch from chronic cigarette smoking, particularly in individuals with asthma and chronic obstructive pulmonary disease (COPD). Evidence on intermediate and long-term carcinogenic effects is lacking. This umbrella review underscores the urgent need for systematic reviews with better adherence to established reporting guidelines, consistent definitions of duration of e-cigarette use, a focus on newer devices, and accounting for the impacts of former or current smoking.