Over the past decade, intra-articular administration of fat-derived orthobiologics (FDO) has emerged as a promising approach for knee osteoarthritis (OA) management. FDO includes cellular stromal vascular fraction (cSVF), tissue stromal vascular fraction (tSVF), and adipose-derived stromal/stem cells (ASCs). Derived from adipose tissue, these biologics provide regenerative potential by leveraging mesenchymal stem cells (MSCs) and their paracrine effects to promote anti-inflammatory, chondrogenic, and regenerative processes. FDOs are administered either via percutaneous injection or arthroscopically guided focal implantation, with promising results in pain relief, functional improvement, and cartilage regeneration as evidenced by magnetic resonance imaging (MRI) and arthroscopy. While mechanically processed tSVF preserves essential extracellular matrix (ECM) components, enhancing cell modulation and differentiation, enzymatically processed cSVF and cultured ASCs offer higher cellular yields but are more regulated. Variability in patient selection, harvesting, processing, and mobilization protocols, as well as assessed clinical parameters poses challenges in interpreting the current literature. Combining FDO with adjunctive treatments, such as platelet-rich plasma (PRP) and fibrin glue, may enhance therapeutic outcomes. Further research is required to optimize dosing, administration techniques, and postoperative protocols to establish FDO’s definitive role in knee OA treatment.