Introduction: Stevens-Johnson syndrome (SJS) is a rare disease that affects the skin, as well as the oral, ocular, and urogenital mucous membranes. This condition is caused by drug reactions in more than 50% of cases. Case presentation: A 20-year-old male visited the emergency service of a tertiary care hospital of Popayán due to a 10-day history of asthenia, adynamia, fever (without objective measurement records), cough with scarce whitish sputum, and headache that improved with paracetamol treatment. However, his condition worsened in the last two days, and he developed hyporexia, pharyngeal pruritus, vesicles, and blisters on the corners of the mouth, the oral mucosa, the trunk, and limbs, as well as breathing difficulty and odynophagia, prompting him to seek medical treatment at the ER. At first, disseminated herpes simplex, systemic lupus erythematosus and SJS were suspected, but based on clinical and laboratory findings, the patient was finally diagnosed with SJS with herpes simplex reactivation associated with the use paracetamol. Consequently, the administration of this drug was stopped and management with acyclovir and methylprednisolone was started. The patient progressed satisfactorily and was discharged 10 days after beginning the new treatment, and his general condition was optimal during follow-up appointments. Conclusion: The occurrence of SJS may be associated with the oral administration of paracetamol; nevertheless, its use is not discouraged due to its great overall benefits. In this sense, given that paracetamol is an over-the-counter drug widely used in Colombia, recognizing the clinical manifestations of SJS is essential to provide adequate management and avoid complications in cases such as the one reported here.