Epidermal growth factor receptor (EGFR) fusions are rare genomic events in non-small-cell lung cancer (NSCLC). With advances in detection technology, some uncommon genomic mutation events, including EGFR fusions, have been detected. There are no standard treatment options for NSCLC patients harboring EGFR fusion. Herein, we report a case of KIF5B-EGFR fusion in NSCLC responding to tyrosine kinase inhibitors (TKIs). A 50-year-old male underwent left upper lobectomy followed by adjuvant chemotherapy for pathological stage IA3 lung adenocarcinoma. The tumor tissue was subjected to next-generation sequencing (NGS) and showed a KIF5B-EGFR fusion. When cancer recurrence occurred thirteen months later, the patient received afatinib (40 mg qd) as second-line treatment, and a partial response was observed, which resulted in an 11-month progression-free survival (PFS). This case provides valuable information on the response to afatinib in an NSCLC patient with a novel KIF5B-EGFR fusion. The NGS assay provides a powerful tool for identifying rare or atypical EGFR gene mutations in patients with NSCLC, which should be encouraged in clinical practice.