Myopathies, joint impairment, muscle spasm, and torn muscles cause an excessive amount of musculoskeletal inflammation, which ultimately causes muscular soreness and stiffness, leading to difficulty in mobility. NSAIDs can suppress the COX enzyme, crucial for converting arachidonic acid into prostaglandin-E2. Oxidative burden increases during impaired health conditions, alleviating and prolonging the inflammatory phase and pain sensation. DA is a widely accepted NSAID that functions as a non-specific inhibitor of COX and is reported to have antioxidant properties. However, it has low solubility and severe adverse effects when used at high doses over a long-term therapy. Thus, the objective of this study is to develop a DA-loaded transferosomal gel with promising anti-inflammatory and antioxidant activity that resembles the commercially available gel, with improved solubility, decreasing the higher dose regimen, minimize potential side effects, and facilitating muscular pain relief over a long period of time. Transferosomes were prepared with a modified thin film hydration technique. The optimized formulation attained the desired particle size, PDI, and zeta potential with high entrapment. The transferosomal gel was investigated for physical characterization, in vitro diffusion, ex vivo permeation, and cellular studies. A cumulative drug release of 92.89 ± 4.21% was achieved after 10 h. The transferosomal gel demonstrated exceptional regulated drug diffusion of 90.68 ± 1.42% over 24 h and permeation of 99.57 ± 6.41% over 48 h. This formulation also exhibited better antioxidant and anti-inflammatory activities than the marketed gel after investigation of in vitro cellular studies. Based on acquired results, it is concluded that DA-loaded transferosomal gel may be potentially effective for reducing musculoskeletal inflammation and providing pain relief.