Background/Objectives: Severe knee osteoarthritis (KOA) is a degenerative disease that significantly affects quality of life (QoL). Although intra-articular (IA) injections of plasma rich in growth factors (PRGF) have proven effective, the subchondral bone plays a crucial role in pathogenesis. The objective of this study was to evaluate the efficacy of intraosseous (IO) PRGF infiltrations in comparison with a saline placebo, followed by the conventional standard treatment of three IA PRGF injections, in enhancing clinical outcomes in patients suffering from severe KOA. Methods: A prospective, randomized, double-blind, multicenter clinical trial was conducted. Eighty-six patients with Kellgren–Lawrence grade III-IV KOA were randomly assigned to two groups: one received an IO infiltration of PRGF and the other received an IO saline solution. Both groups subsequently received three IA PRGF injections. Clinical outcomes were assessed using the KOOS and WOMAC scales at baseline and at 3, 6, and 12 months. Results: Both groups showed a statistically significant improvement in all KOOS and WOMAC subscales at all follow-up points compared to their baseline values. However, the group that received the IO PRGF infiltration demonstrated significantly greater improvements in nearly all domains of the KOOS and WOMAC scales (pain, symptoms, function, and quality of life) at 3, 6, and 12 months compared to the saline group (p < 0.05). No serious adverse events were recorded. Conclusions: The combination of intraosseous and intra-articular PRGF infiltrations is a superior therapeutic strategy to the combination of intraosseous saline solution and intra-articular PRGF for treating severe KOA. These findings suggest that treating the subchondral bone directly with PRGF has a significant and clinically relevant therapeutic effect, resulting in greater pain reduction and functional improvement at one-year follow-up.