Osteoarthritis (OA) of the knee affects millions of people with sizable socioeconomic burden. Conventional treatment modalities are prioritized, turning to surgical intervention only when they have failed. However, these traditional modalities have shortcomings, only aiming to reduce pain rather than targeting the underlying pathophysiology. Recently, the use of biologics, including autologous peripheral blood-derived orthobiologics (APBOs), has increased and demonstrated great promise for the management of knee OA. Platelet-rich plasma (PRP) is the most widely used APBO, but its efficacy is still uncertain, attributed to lack of standardized formulation protocols, characterization, and patient variables. To overcome the limitations posed by PRP, the use of other APBOs such as platelet lysate (PL) has been considered. This review summarizes the outcomes of clinical studies involving PL to manage OA of the knee. Multiple databases (Scopus, Embase, PubMed, and Web of Science) were searched employing terms "platelet lysate" and "knee osteoarthritis" for articles published in the English language to August 15, 2024, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Only three clinical studies fulfilled our search and inclusion criteria. Intra-articular injection of three doses of PL injected every 3-4weeks is safe and efficacious, resulting in statistically significant improvements in different patient-reported outcome measures at 6-12months follow-up. The existing published peer-reviewed literature suggests that intra-articular injection of PL is safe and can decrease pain and increase function in patients with knee OA. Nonetheless, given the dearth of pertinent literature, more adequately powered, multicenter, prospective, non-randomized and randomized controlled studies with extended follow-up are needed to confirm the effectiveness of PL in knee OA. Further comparative studies to help clinicians in choosing the best APBO for knee OA treatment are also warranted.