<p>Temporomandibular joint (TMJ) disc displacements (DD) and osteoarthritis (OA) are types of intra-articular temporomandibular disorders (iTMDs) commonly accompanied by pain and dysfunction. We systematically evaluated the literature to determine the comparative effectiveness of treatments for painful iTMDs. We searched seven databases for randomized clinical trials (RCTs) evaluating the effect of medications, used alone or adjunctively, on pain intensity and mouth opening. Risk of bias and certainty of evidence were assessed using Cochrane’s RoB 2.0 tool and the CINeMA approach. Data were synthesized using frequentist network meta-analyses. We included twenty-three RCTs involving 1264 patients. In TMJ-DDs, multiple interventions demonstrated statistically significant short-term (≤ 3 months) pain reductions, with only MESNA (sodium 2-mercaptoethanesulfonate) and arthrocentesis with hyaluronic acid (HA) also showing statistically significant effects in the long-term (&gt; 3 months). Several interventions were also associated with statistically significant improvements in mouth opening. In TMJ-OA, palmitoylethanolamide and avocado-soybean extract showed statistically significant short-term pain reductions, while glucosamine hydrochloride or glucosamine sulfate combined with HA were associated with statistically significant long-term improvements in pain and mouth opening. No intervention showed significant short-term effects on mouth opening in TMJ-OA. For both TMJ-DD and OA, estimates were generally supported by low or very low certainty of evidence and were below the minimal clinically important difference. Overall, the evidence indicates limited and inconsistent clinical benefits, and no available treatment can be recommended with confidence. This study highlights the urgent need for additional high-quality RCTs to generate robust and clinically meaningful evidence to guide practice in painful iTMDs.</p>