Knee osteoarthritis (OA) significantly impacts global health, causing pain, disability, and socioeconomic burden. Traditional treatments often provide only temporary relief and can have adverse effects. Autologous conditioned serum (ACS) therapy, which enriches a patient's own blood with growth factors and anti-inflammatory cytokines, has emerged as a promising approach to manage knee OA, potentially offering pain reduction, improved function, and tissue regeneration. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched databases such as PubMed, Web of Science, and Cochrane using terms like "Autologous Conditioned Serum" and "knee osteoarthritis." Clinical studies were selected based on their focus on ACS's efficacy in knee OA, assessing outcomes like pain relief, functional improvement, and adverse events. Eighteen studies met the inclusion criteria, including randomized controlled trials, observational studies, and comparative analyses. The review included a wide range of study designs and outcomes, highlighting ACS's efficacy in reducing pain and enhancing knee function as evidenced by various patient-reported outcome measures Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Society Clinical Rating Score (KSCRS) with a follow-up of up to 11 years (range: 2-11 years). Comparative studies showed ACS to be as effective or superior to conventional treatments such as platelet-rich plasma, steroids, and hyaluronic acid, especially in cases of moderate synovitis. Minimal adverse effects such as peri-injection pain, rigidity, synovitis, transient sensation of redness/heat, and numbness in the knee/leg/toes were reported, underscoring ACS's safety. Some studies suggested ACS might also have disease-modifying effects, contributing to tissue repair and integrity. ACS therapy offers a promising alternative for knee OA management, demonstrating potential benefits in symptom alleviation, functional improvement, and safety. Indications of disease-modifying properties further highlight its therapeutic value. However, the need for standardized formulations and treatment protocols, long-term studies, and mechanistic understanding remain. Future research should focus on addressing these gaps to fully elucidate ACS's role in the treatment landscape of knee OA.