OBJECTIVES: The use of antidepressants has been increasing in the US and Canada since 2000. However, the laws and process for reviewing and approving new drugs vary among these two countries. These different regulations affect health care professionals and patients as well as manufacturers regarding a product’s development, approval, and post-marking activities. The objective of this study was to provide a comparative analysis of antidepressant drugs approved by the U.S. Food and Drug Administration (FDA) and Health Canada (HC). METHODS: The FDA and HC websites were used to obtain the data on antidepressant drugs’ indications, contraindications, approval dates, market status, dosage forms, strengths, and route of administrations. Descriptive statistics and t-test were performed. RESULTS: From 1959 to 2015, a total of 35 antidepressant drugs were identified, 33 were approved by FDA while 30 drugs were approved by HC. Among the 25 drugs marketed in both countries, the majority (16 drugs, 64%) were approved by FDA first and the rest were approved by HC first. The average number of approved indications for antidepressant drugs by the FDA (2.24±1.9) was not statistically different from HC (2.12±1.7). The FDA approved more indications in 4 drugs (16%), and HC did the same in another 4 drugs (16%), and each agency approved different indications in 2 (8%). HC’s average number of contraindications (4.46±3) was significantly higher than FDA’s (3.6±3.4). There were also differences in restrictions of use (56%), limitations of use (40%), use in pediatric (24%), dosage forms (44%), and strengths (80%). CONCLUSIONS: There are significant differences in the number of antidepressant drugs approved by both agencies. In addition, differences in indications, contraindications, and other characteristics of drugs were identified. The differences may lead to differences in access to treatments. There is a need to make drug evaluations transparent to identify the root causes of these differences.