Background: One in five Americans turn to TikTok before calling their own physician. Objective: With social media on the rise as a source of health-related information, we aimed to investigate and evaluate popular content about mast cell activation syndrome (MCAS) on TikTok. Methods: Between June 14 and 16, 2024, four different MCAS-relevant phrases were searched on TikTok, and the top 50 most watched videos were analyzed independently by three subinvestigators. The global quality score (GQS) (range from 1 to 5) was applied to assess the value of the educational videos. The profession of the content creator, use of MCAS Vienna diagnostic criteria, association with postural orthostatic syndrome (POTS)/Ehlers Danlos syndrome (EDS), and information trends were also analyzed. Results: The 50 most watched MCAS-related videos collectively had > 6.5 million views, and the average number of views per video was 131,500. Most videos were created by health-care professionals (58%), including physicians (26%) and other health-care professionals (32%), whereas the minority were created by non-health-care professionals (42%). Only one video included the MCAS Vienna criteria (2%), and 12 videos associated MCAS with POTS and/or EDS (24%). The average GQS was 1.94 (SD 0.34). Common MCAS misinformation trends included the following: inaccuracy of symptoms, diagnostic criteria, triggers, and treatment options. Conclusion: Most MCAS videos on TikTok contained misinformation, did not include key diagnostic criteria, and had poor GQS. The most viewed videos were primarily created by health-care professionals. Patients and health-care providers need to be aware of the quality of health-care information on social media.