One of the most common reasons for failure of primary total knee arthroplasty and need for revision surgery is periprosthetic infection. Antibiotics are one of the mainstays of treatment to address prosthetic joint infections, but the route of administration and timing of delivery to optimize patient outcomes are debated. This article reviews the use and attributes of commonly used oral antibiotics, especially extended or long-term utilization, as prophylaxis and treatment for prosthetic joint infections in a primary or revision total knee arthroplasty, which include debridement, antibiotics, and implant retention, one-stage and two-stage exchange arthroplasty.