Introduction: Tuberous sclerosis complex (TSC) is a rare congenital disorder often associated with epilepsy. However, real-world treatment patterns for epilepsy in patients with TSC are not yet well categorized. Methods: This study included patients with TSC and epilepsy from fifteen clinics in the United States and one in Belgium who were enrolled in the TSC Natural History Database (2006–2014). Patient demographics and epilepsy treatment patterns, including the use of anti-epileptic drugs (AEDs), epilepsy surgeries, and dietary therapies were assessed. Results: Of the 1328 patients with TSC in the database, 1110 (83.6%) were diagnosed with epilepsy. The median age of epilepsy diagnosis was 0.7 years. Of those who received treatment for epilepsy (92.3%), 99.5% were prescribed AEDs, 25.3% underwent surgery, 7.9% were prescribed special diets, and 1% were prescribed mammalian target of rapamycin (mTOR) inhibitors. Of the patients receiving AEDs, over half (64.5%) used ≥3 different AEDs, and 22.5% underwent surgical treatment following AED initiation. Of the patients who underwent surgery, 35.1% had subsequent surgery. Conclusion: The use of multiple AEDs and surgical interventions may indicate a need for new therapies to reduce the treatment burden among patients with TSC and epilepsy.