The incidence and rates of diagnosis of drug-induced liver injury (DILI) have been increasing in recent years as findings from basic research and the examination of clinical databases reveal information about the clinical course, etiology, and prognosis of this complex disease. The prevalence of metabolic comorbidities (e.g., diabetes mellitus, fatty liver, obesity, and metabolic syndrome (MetS)) has been increasing during the same period. The results of preclinical and clinical research studies indicate that characteristics of metabolic comorbidities are also factors that affect DILI phenotype and progression. The objective of this review is to present the evidence for DILI and hepatotoxicity mechanisms, incidence, and outcomes in patients with MetS and nonalcoholic fatty liver disease. Moreover, we also summarize the relationships between drugs used to treat metabolic comorbidities and DILI.