Pneumatosis intestinalis (PI) is a rare radiological finding given by the presence of gas within the bowel wall, mainly caused by endoscopic procedures, infections and other gastrointestinal diseases. To date, cytotoxic chemotherapeutic agents, immunotherapy drugs and monoclonal antibodies used for molecular targeted therapy in oncological patients have been reported as a possible cause of PI, but their role remains unclear. We hereby report the case of a 61-year-old patient with stage IV lung adenocarcinoma in treatment with afatinib—a tyrosine kinase inhibitor (TKI), since the diagnosis, who presented to the emergency department with abdominal pain secondary to left-colonic PI. A conservative treatment with drug suspension was successfully attempted. To the best of our knowledge, even though many monoclonal antibodies are associated with this condition, this is the first case report of PI likely induced by afatinib. Although PI is extremely rare, clinicians should be aware of the risk of PI in patients undergoing afatinb therapy and the present case represents a significant warning to differentiate the associated conditions of PI and evaluate whether or not emergency surgery is actually necessary. Therefore, abdominal symptoms in patients receiving oncological treatments should not be overlooked, and clinicians should not hesitate to request targeted radiological investigations to facilitate early diagnosis and management of PI. Timely event detection is imperative to optimal management and to prevent further deterioration, recurrent PI, or even perforation, especially in oncological patients.