Stevens-Johnson syndrome (SJS) is a life-threating mucocutaneous reaction predominantly induced by drugs. Targeted cancer therapies such as pembrolizumab, which has been approved for the treatment of metastatic malignancy, can cause severe skin toxicities, including SJS. They are rare and inconsistently reported. In this article, we report the case of a 80-year-old woman with metastatic non-small cell lung cancer who had a SJS-like eruption involving oral mucosa after 15 weeks of exposure of pembrolizumab (6 doses) and 7 days after 1 dose of recombinant zoster vaccine. SJS is a rare blistering disorder with high mortality rate and significant morbidity. Causes include drugs, herpes viruses, and immunization. The timing of the eruption soon after the receipt of recombinant zoster vaccine suggests a role of vaccination in our patient, yet patients receiving cancer immunotherapy may develop late-onset skin toxicity. Therefore, we recommend long-term monitoring for mucocutaneous reactions after initiation of pembrolizumab. Further research is needed to characterize the immunological pathogenesis and improve timely recognition and treatment strategies.