Background: The EQ-5D-5L is a generic preference-based questionnaire developed by the EuroQol Group to measure health-related quality of life (HRQoL) in 2005. Since its development, it has been increasingly applied in populations with various diseases and has been found to have good reliability and sensitivity. This study aimed to summarize the health utility elicited from EQ-5D-5L for patients with different diseases in cross-sectional studies worldwide.Methods: Web of Science, MEDLINE, EMBASE, and the Cochrane Library were searched from January 1, 2012, to October 31, 2019. Cross-sectional studies reporting utility values measured with the EQ-5D-5L in patients with any specific disease were eligible. The language was limited to English. Reference lists of the retrieved studies were manually searched to identify more studies that met the inclusion criteria. Methodological quality was assessed with the Agency for Health Research and Quality (AHRQ) checklist. In addition, meta-analyses were performed for utility values of any specific disease reported in three or more studies.Results: In total, 9,400 records were identified, and 98 studies met the inclusion criteria. In the included studies, 50 different diseases and 98,085 patients were analyzed. Thirty-five studies involving seven different diseases were included in meta-analyses. The health utility ranged from 0.31 to 0.99 for diabetes mellitus [meta-analysis random-effect model (REM): 0.83, (95% CI = 0.77–0.90); fixed-effect model (FEM): 0.93 (95% CI = 0.93–0.93)]; from 0.62 to 0.90 for neoplasms [REM: 0.75 (95% CI = 0.68–0.82); FEM: 0.80 (95% CI = 0.78–0.81)]; from 0.56 to 0.85 for cardiovascular disease [REM: 0.77 (95% CI = 0.75–0.79); FEM: 0.76 (95% CI = 0.75–0.76)]; from 0.31 to 0.78 for multiple sclerosis [REM: 0.56 (95% CI = 0.47–0.66); FEM: 0.67 (95% CI = 0.66–0.68)]; from 0.68 to 0.79 for chronic obstructive pulmonary disease [REM: 0.75 (95% CI = 0.71–0.80); FEM: 0.76 (95% CI = 0.75–0.77)] from 0.65 to 0.90 for HIV infection [REM: 0.84 (95% CI = 0.80–0.88); FEM: 0.81 (95% CI = 0.80–0.82)]; from 0.37 to 0.89 for chronic kidney disease [REM: 0.70 (95% CI = 0.48–0.92; FEM: 0.76 (95% CI = 0.74–0.78)].Conclusions: EQ-5D-5L is one of the most widely used preference-based measures of HRQoL in patients with different diseases worldwide. The variation of utility values for the same disease was influenced by the characteristics of patients, the living environment, and the EQ-5D-5L value set.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020158694.