The present study investigated the passive transdermal delivery of 3-fluoroamphetamine hydrochloride (PAL-353) and evaluated the effects of chemical and physical enhancement techniques on its permeation through human skin. In vitro drug permeation studies through dermatomed human skin were performed using Franz diffusion cells. Passive permeation of PAL-353 from propylene glycol and phosphate buffered saline as vehicles was studied. Effect of oleic acid, maltose microneedles, ablative laser, and anodal iontophoresis on its transdermal permeation was investigated. Infrared spectroscopy, scanning electron microscopy, calcein imaging, confocal laser microscopy, and histology studies were used to characterize the effects of chemical and physical treatments on skin integrity. Passive permeation of PAL-353 (propylene glycol) after 24 h was found to be 1.03 ± 0.17 μg/cm2. Microneedles, oleic acid, and laser significantly increased the permeation to 7.35 ± 4.87 μg/cm2, 38.26 ± 5.56 μg/cm2, and 523.24 ± 86.79 μg/cm2 (p < 0.05), respectively. A 548-fold increase in drug permeation was observed using iontophoresis as compared to its passive permeation from phosphate buffered saline (p < 0.05). The characterization studies depicted disruption of the stratum corneum by microneedles and laser treatment. Overall, transdermal permeation of PAL-353 was significantly enhanced by the use of chemical and physical enhancement techniques.