Most patients can be cured of Lyme disease with a course of oral antibiotics lasting two to three weeks. Commonly used antibiotics include doxycycline, amoxicillin, or cefuroxime axetil. Patients with neurological or cardiac complications may require intravenous treatment with antibiotics such as ceftriaxone or penicillin. Some patients may require a second course of antibiotics lasting four weeks, especially if they did not begin treatment until the late stage of the disease.

The Food and Drug Administration (FDA) has issued a warning about injectable bismacine, an alternative medicine sold as a treatment for Lyme disease. This compound is not approved for injection and its use may lead to heart and kidney failure.