There is an ongoing interest in alternatives to total knee arthroplasty, as a means to delay inevitable replacement. A possible, minimally invasive, alternative is a sub-chondroplasty, involving interosseous injection of bone substitute materials such as calcium phosphate (CaPo4), platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC) or Injectable demineralized bone matrix (iDBM) into the subchondral bone. Eleven clinical trials were found, investigating the effectiveness of sub-chondroplasties performed using CaPo4, PRP, BMAC, and iDBM. A non-stratified and stratified meta-analysis of the included studies were conducted to test for confounding variables across the trials. Non-stratified analysis, regardless of injectable type, revealed a significant improvement in the average Visual Analog Scale (VAS) score and postoperative Knee Injury and Osteoarthritis Outcome Score (KOOS) in patients post sub-chondroplasty, as compared to baseline. This analysis demonstrates that the sub-chondroplasty procedure reduces pain, improves function, and has lower risk of conversion to arthroplasty. (Journal of Surgical Orthopaedic Advances 32(2):065-074, 2023).