Background. Knee osteoarthritis is a common disease with increasing incidence and prevalence in western countries. It can cause severe pain and functional limitations, thereby representing a threat for patients’ quality of life and a burden for national health systems. Intra-articular injections with hyaluronic acid (HA) and platelet-rich plasma (PRP) have been used for decades in order to reduce the symptoms caused by osteoarthritis. In recent years, a combination of HA and PRP has been introduced in clinical practice with the aim to minimize the clinical presentation of osteoarthritis and potentially delay articular degeneration. Materials and Methods. Sixty cases with grade II-III knee osteoarthritis according to the Kellgren–Lawrence classification were included in a prospective study, focused on the evaluation of clinical and functional outcomes after intra-articular knee injections. Cases were randomly divided into three groups. Twenty cases (Group A) were injected with HA, 20 (Group B) had PRP, and the remaining 20 (Group C) received a combination of HA and PRP. Basal WOMAC score and VAS score were recorded before the treatment and repeated within 3 and 6 months after the treatment. Results. At 6-month follow-up, Group C (PRP + HA) was the one with the lowest WOMAC and VAS mean values. It was also the only group that reported a reduction in the two values both in the first three months and in the following three months. No major complication was recorded. Conclusion. The combination of platelet-rich plasma and hyaluronic acid can be effective in the treatment of grade II-III knee osteoarthritis in a short-to-mid-term scenario. It represents an innovative and valuable alternative to the administration of its two components alone.