The onset of Lennox-Gastaut syndrome (LGS), a severe epilepsy syndrome, is typically before 8 years of age. Late-onset LGS (with onset in adolescence and adulthood) is relatively rare clinically and has some differences from classical LGS. Herein, we describe the case of a patient with late-onset LGS and provide a literature review of such cases. The patient had focal epilepsy onset at 8 years of age. After a 9-year evolution, he suffered seizures of different types and had a diagnosis of late-onset LGS. Drug treatment was ineffective. Nothing was found on stereotactic electroencephalography (SEEG) and magnetic resonance imaging (MRI) during the course of the disease. After the second presurgical evaluation, we found a suspicious focus on high-resolution structural MRI which was verified by SEEG at last. After SEEG-guided radiofrequency thermocoagulation (RFTC), his seizures were controlled, and his cognitive function and quality of living clearly improved. However, his seizures recurred 2 years later, and he underwent left occipital resection. Thereafter, his seizures have been controlled until now. This case emphasizes the importance of high-resolution structural MRI in the treatment of LGS. Furthermore, it suggests that late-onset LGS may be caused by focal lesions and evolve from focal epilepsy. Thus, characterizing the clinical symptoms and performing individualized electroencephalographic follow-up are both very important. Additionally, the clinical outcome in this case implies the value and limitations of RFTC in patients with epilepsy and a clear focal lesion. Moreover, this case further supports differences between late-onset and classical LGS in terms of clinical manifestation, cognitive changes, prognosis, and treatment.