The Janus kinase inhibitor tofacitinib (TOF) is an FDA-approved drug for rheumatoid arthritis (RA) treatment, but its long-term oral use leads to significant systemic side effects. The present research aimed to conquer these challenges by formulating hyaluronic-acid-coated transethosomes (HA-TOF-TE), a novel system for targeted, topical delivery of TOF to reduce systemic toxicity and improve therapeutic efficacy. Transethosomes were synthesized via the cold sonication technique with HA functionalization enabling CD44 receptor-mediated targeting of inflamed synovial tissue. Optimized TOF-TE and HA-TOF-TE formulations showed particle sizes of 199.08 ± 4.2 and 151.5 ± 5.4 nm, zeta potentials of -27.1 ± 0.75 and -34.10 ± 0.89 mV, and entrapment efficiencies of 81.16 ± 0.84% and 79.19 ± 2.65%, respectively. The gels were assessed through