The aim of this study is to investigate clinical and radiographic outcomes of a biomimetic scaffold for the treatment of osteochondral knee lesions in patients with early OA. Study population was represented by 26 patients with a mean age of 44 years affected by early OA. Inclusion criteria were two episodes of knee pain for more than 10 days in the last year, Kellgren-Lawrence OA grade 0 or I or II, and arthroscopic findings of cartilage defects. Nineteen patients had a previous surgery, 11 of which were revision surgeries of osteochondral unit. All patients were treated with a biomimetic scaffold with a tri-layered structure of type I equine collagen and magnesium-enriched hydroxyapatite. Clinical outcomes were evaluated using the IKDC, Lysholm, VAS, KOOS, and Tegner scores at baseline and at an average follow-up of 35 months. Magnetic resonance imaging (MRI) was performed at follow-up time in 19 patients. Clinical outcomes showed significant improvement in VAS, Lysholm, IKDC subjective score, and KOOS subscales in 69% of the patients. Complication rate of this cases series was 11%, with no surgical failure, although 31% of patients did not reach a significant improvement and were thus considered as clinical failure. MRI analysis showed integration of the scaffold only in 47% of the patients, with partial regeneration of the subchondral bone. No correlation between clinics and radiological images was found. The use of a biomimetic osteochondral scaffold in the setting of an early OA, alone or associated with other procedures, appeared to be a valid and safe option, able to provide good and stable clinical outcomes with high patient's satisfaction and low complication rate.