The treatment of Lyme disease requires the use of antibiotics. In cases where an EM rash is present, treatment should begin immediately. Blood tests are not recommended because they are often falsely negative. Most studies on the treatment of early Lyme disease used at least 20 days of antibiotic therapy. Treatment is usually successful; overall cure rates for this stage are roughly 90%.

Late Lyme disease is much more difficult to treat and while most patients improve with antibiotic therapy, cure rates are much lower. The duration of treatment can be quite long; some patients may need to be on antibiotics for months or even years. Others may require intermittent courses of antibiotics. Each case is unique and care need to be individualized. A true EM rash does not last for only a few days. An untreated EM expands and regresses over weeks; the clearing is much faster if antibiotics are given.