Burning mouth syndrome (BMS) or stomatodynia is characterized by a spontaneous burning pain in the oral mucosa without known cause or recognized treatment. This double-blind, randomized, placebo-controlled, single-center study evaluated the effects of systemic Hypericum perforatum extract in patients with BMS. Forty-three patients participated, of whom 39 (35 women, four men, aged 64.9 ± 4.7 years) completed the study. The patients took indistinguishable 300-mg capsules containing either H. perforatum extract (hypericin 0.31% and hyperforin 3.0%) or placebo three times a day for 12 weeks. The intensity of burning pain was evaluated using a 10-cm visual analog scale (VAS) before the first dose and at visits after 4, 8, and 12 weeks. Furthermore, we also recorded the number of oral mucosa sites with reported burning symptoms and the self-reported descriptions of the patient’s condition before and after the treatment. Pain, measured using the VAS, was similar at the beginning of the study and even though a slightly better performance in the test group, the difference was not statistically significant (P = 0.2216). The results failed to demonstrate that 300 mg of H. perforatum extract taken three times a day for 12 weeks improved the pain of BMS patients, although the general reduction in the number of sites with reported burning sensation, a less accurate and objective score, was significant.