Background <p>Inflammatory nail disorders can have a significant impact on patients’ quality of life owing to aesthetic and functional concerns. They are also challenging to treat because the therapeutic armamentarium is quite limited. This systematic review aims to report the efficacy and safety of Janus kinase and Tyrosine kinase 2 inhibitors in treating these conditions.</p> Methods <p>We conducted a comprehensive search on PubMed, Cochrane, and Embase Library to find eligible case reports, case series, single-arm clinical trials, and randomized controlled trials. We used the following search terms from inception until 15 December, 2024: “nail” AND “jak inhibitors” OR “tofacitinib” OR “baricitinib” OR “abrocitinib” OR “ruxolitinib” OR “deuruxolitinib” OR “upadacitinib” OR “ritlecitinib” OR “deucravacitinib” (nine searches in total).</p> Results <p>Of 441 articles found, 31 were included in this study. The most extensively studied drug was tofacitinib, followed by baricitinib, deucravacitinib, upadacitinib, and abrocitinib. Janus kinase/Tyrosine kinase 2 inhibitors demonstrated improvements in inflammatory nail conditions, with generally mild adverse events (nasopharyngitis and transient laboratory abnormalities being most common). The topical formulation of tofacitinib, the only one studied in these nail diseases, also demonstrated promising results with minimal systemic absorption and no side effects.</p> Conclusions <p>This review highlights Janus kinase/Tyrosine kinase 2 inhibitors as a valuable addition to the therapeutic arsenal for inflammatory nail disorders while emphasizing the importance of safety assessments and tailored treatment approaches. The long-term safety of Janus kinase/Tyrosine kinase 2 inhibitors still needs further investigation and the potential for adverse events emphasizes the need for tailored therapeutic strategies, including more studies on topical formulations.</p>