The transdermal absorption of drugs and its subsequent deep tissue delivery is a complex process, with many factors influencing the penetration mechanisms. Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in the treatment of joint and muscle diseases. However, the dangers associated with oral medications highlight the need for alternative methods of targeting and retaining drugs; one such means is through topical delivery. The drug's lipophilicity, permeability, and fraction unbound found in the viable skin are some physiochemical factors influencing the delivery mechanism after transdermal absorption. These and other variables play a role in determining whether the drug reaches the deep tissues via direct penetration or from systemic redistribution. Pharmacokinetic models have been developed to help elucidate the penetration routes and efficacy for various drugs. While there are still uncertainties regarding the deep tissue penetration kinetics, improvements to current research methodologies may bring about a greater understanding of percutaneous absorption into the deep muscle and joints.