Nefopam hydrochloride, a nonsteroidal anti-inflammatory drug, is administered in tablet form three times daily or as intramuscular injection at 6-h intervals to treat disorders such as acute or constant pain. It is also used for a prolonged treatment of severe pain, when morphine therapy has to be withdrawn for morphine-related dependence. To achieve a constant drug-plasma level of nefopam for a prolonged period, a transdermal drug delivery system was fabricated in our present study by employing suitable experimental hydrophilic and lipophilic polymeric combinations of polyvinyl pyrrolidone (PVP) and ethyl cellulose (EC). Physical studies including weight variation, moisture content, moisture uptake, flatness, external morphology of the formulations, and in vitro drug release were performed. Drug-excipient interaction studies were carried out using Fourier transform infrared spectroscopy. In vitro skin permeation study with cadaver skin was conducted using modified Keshary-Chein diffusion cells. Interactions between nefopam and PVP seem to contribute to the slow and controlled release pattern of nefopam. The scanning electron microscopy evaluation of prepared matrix patches revealed that drug was dispersed uniformly in polymeric matrix. In vitro drug release study showed that an increase in concentration of hydrophilic polymer, PVP, enhanced drug release substantially. In vitro skin permeation study showed variable permeation profiles of nefopam from the experimental patches. Among the formulations, PVP:EC (1:3) was found to provide slowest release and maximum sustained skin permeation of drug in vitro. Application of those patches, PVP:EC (1:3), on human volunteers was found to provide systemic availability of the drug till 48 h.