Introduction Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the USA, and a major cause of medication discontinuation. However, DILI is often under-diagnosed, primarily due to the lack of agreed upon diagnostic criteria and limiting coding nomenclature. Previous attempts to address these issues have met with only partial success. Methods We conducted a retrospective observational analysis of demographic, clinical, and laboratory data for 55 patients hospitalized in an Israeli tertiary care medical center between 2005-2017 and diagnosed with DILI. Results We identified 55 patients hospitalized with DILI over 12 years. DILI was associated with female gender, and more patients were ≥ 50 years of age. Hepatocellular liver injury was the most common type of liver injury (49.0%). Common clinical manifestations included fever (41.8%), weakness (41.8%) and jaundice (34.5%). The major offending drug group was antibiotics (35.0%) with amoxicillin and clavulanate the most common single drug within the group (7.2%). Most cases were caused by drugs administered orally (84%), while most cholestatic injury was seen with intravenous administration. De Ritis ratio (AST/ALT) was above 1.0 in 75% of cases. Conclusions Most DILI was caused by oral antibiotics. The incidence of DILI in our study was low, possibly due to under-diagnosis or misclassification. The adoption of the updated international classification of disease 10th edition (ICD-10) may improve reporting rates. Utilization of the De Ritis ratio may help to differentiate between DILI and viral hepatitis.