Pelvic inflammatory disease (PID) is a clinical syndrome ensuing infection-induced inflammation of the upper reproductive tract in females. It is mostly characterized by chronic pelvic pain and can lead to severe outcomes like tubal-factor infertility or ectopic pregnancy. The treatment primarily focuses on eradication of infection and control of the inflammatory consequences. Nonsteroidal anti-inflammatory drugs (NSAIDs) are most commonly used for the control of inflammation, but their use is limited by adverse effects, especially when used in the long-term. Systemic Enzyme Therapy (SET) using a combination of Trypsin-Bromelain-Rutoside have a long history of clinical use in various inflammatory conditions, including PID. It is an effective alternative to conventional therapies for managing the symptoms and preventing the complications of PID. SET moderates the inflammatory response, prevent scar formation and adhesions. The various mechanisms by which SET acts on the relevant pathophysiology of PID have been presented in this review. Results from clinical studies have also been discussed, including comparative studies of SET against placebo or conventional anti-inflammatory agents, and when given concomitantly with antibiotics versus antibiotics alone in a variety of acute and chronic PID-related conditions.