Platelet-rich plasma (PRP) has been widely used as an adjunctive tool in surgical tissue repair and, more recently, as a percutaneous approach to stimulate tissue regeneration. Among its applications, PRP stands out in the treatment of musculoskeletal disorders, including knee chondral lesions, osteoarthritis, tendinopathies, and soft tissue injuries. However, robust evidence is still required to establish standardized clinical use of PRP, especially when combined with other therapies. This study aimed to evaluate the efficacy of intra-articular infiltration of PRP combined with hyaluronic acid (HA) in the treatment of knee chondral lesions. A total of 313 patients were included and evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and Short Form Health Survey (SF-12 scores), with a 12-month follow-up. The results showed statistically significant improvement (p < 0.0001) at all evaluated time points, with an average gain of up to 90 points in joint function and quality of life scores by the end of follow-up. The combined PRP and HA treatment provided progressive and sustainable clinical benefits, proving to be an effective and safe alternative for chondral regeneration and symptom relief in the knee.