This article addresses the best practice in managing osteoarthritis (OA), weighing the benefits and risks of various intra-articular therapies. For many decades we had used intra-articular injections of corticosteroids (IACSs) as the only option after analgesics and physical therapy to help symptoms in patients who suffer from mild to moderate OA until they get ready for joint replacement. In advanced degenerative diseases, particularly in the elderly, we go directly to surgery except when there are multiple comorbidities, then surgery is not an option; thus, IACS injection is the only option left. Furthermore, in individuals suffering from renal disease, peptic ulcer, diabetes, or heart failure, we cannot use regular non-steroidal anti-inflammatory medicines, going the only option for frequent IACSs. Several kinds of literature suggest some harmful effects of IACSs. These include accelerated OA of the cartilage, subchondral insufficiency fracture, joint infection, and osteonecrosis. As the science progresses, regenerative therapies (RTs) emerge, including hyaluronic acid (HA), platelet-rich plasma (PRP), and mesenchymal stem cell (MSC) therapy. RTs carry an excellent safety profile compared to IACSs. That shift in paradigm by moving away from using IACSs in OA to those RTs has shown more prolonged symptomatic effects, slowing or stopping the progression of OA and sometimes regeneration of the cartilage and surrounding tissues.