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Antibiotics are among the most common causes of drug-induced liver injury worldwide. Amoxicillin/clavulanic acid and nitrofurantoin are the most common culprits while tetracyclines are a rare cause of liver injury. Among tetracyclines, minocycline has been reported more frequently than doxycycline, which is an extremely rare cause of drug-induced liver injury. We present a healthy 28-year-old male patient from rural United States who was taking doxycycline for Lyme disease. After five days of therapy, he developed nausea, vomiting, fatigue, and significant transaminitis consistent with a hepatocellular pattern of liver injury. After a thorough workup which ruled out other causes such as infection, autoimmune diseases, liver malignancy, and vascular, structural, and metabolic disorders, his liver injury was attributed to doxycycline. We reached the diagnosis also by demonstrating a consistent temporal association between doxycycline intake and liver injury and the patient recovered completely with the cessation of doxycycline. Recognition of doxycycline as a cause of drug-induced liver injury should be considered in patients utilizing this antibiotic. Doxycycline, unlike minocycline, has a short latency period. Early recognition and discontinuation of doxycycline in our patient resulted in the complete resolution of symptoms and transaminitis preventing further morbidity and mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Nikolajevic et al.)