Autologous bone marrow concentrate (BMC), platelet-rich plasma (PRP), and platelet lysate (PL) have emerged as promising orthobiologic treatment options for knee osteoarthritis (OA). The present observational study reports minimal clinically important difference (MCID) and substantial clinical benefit (SCB) values for several patient-reported outcome measures (PROMs) used to monitor changes in joint pain and function following percutaneous treatment of knee OA with a combination of BMC and platelet products (n = 295 knees). Distribution-based approaches were used to determine 12-month MCID values for the International Knee Documentation Committee (IKDC) subjective, Lower Extremity Functional Scale (LEFS), Numeric Pain Scale (NPS), and modified Single Assessment Numeric Evaluation (SANE) scores. Alternatively, a within-cohort, anchor-based approach, leveraging the modified SANE as a global transition question, was used to determine MCID values of 12.2, 8.4, and - 1.8, and SCB values of 29.5, 22.5, and - 3.0 for IKDC, LEFS, and NPS, respectively. Approximately 87% of treated knees reported change scores that met or exceeded an MCID value while 59% reported change scores that met or exceeded an SBC value for one or more PROMs. In reporting MCID and SCB values for PROMs following the treatment of knee OA with a combination of BMC and platelet products, we sought to provide a foundation for assessing the clinical efficacy of orthobiologic interventions in this developing field.