Obesity and non-alcoholic fatty liver disease (NAFLD) are “lifestyle diseases” related to harmful habits, affecting a large portion of the global population at a steadily increasing prevalence. These disorders are inextricably associated with each other and therapeutic lifestyle changes (TLC) remain the cornerstone of their management. Nevertheless, TLC are difficult to achieve or maintain, and the use of medicines is often suggested. Different categories of medicines have been proposed, many of which are not officially licensed for these conditions. For NAFLD in particular, no drug with official indication exists so far. Thus, it is important that clinicians are aware of the quality of evidence supporting the efficacy of drugs before a decision to treat. To assist rational medical decision, in the present systematic review, we sought to evaluate the quality of evidence from phase III/IV clinical trials of major drugs currently proposed for obesity and NAFLD.