Purpose <p>Based on formulation optimization and pharmacokinetic (PK) assessment, an atomoxetine biphasic dissolving microneedle (DMN) system was developed. The system exhibits satisfactory mechanical properties and demonstrates an absorption profile superior to that of the oral dosage form.</p> Methods <p>A mechanically robust and rapidly DMN system was fabricated using a composite of pullulan (PL) and Gantrez AN-119 (GAN-119), with a polystyrene (PS) backing integrated to prevent drug migration. Comprehensive analyses were conducted to characterize the morphology, mechanical strength, hygroscopicity, drug content, and in vitro dissolution rate of the MNs. Furthermore, the pharmacokinetic profile of the DMN formulation was evaluated in rats and compared with that of oral administration at an equivalent dose, to assess the DMN’s potential for clinical application.</p> Results <p>A casting solution with PL-to-GAN-119 ratio of 4:1 provided optimal mechanical strength to the DMN tips, achieving 100% insertion efficiency. The use of a water-insoluble PS backing effectively prevented drug migration into the backing layer and significantly enhanced transdermal drug delivery. In vivo pharmacokinetic studies showed that the DMN group exhibited a T_max of 1.0&#xa0;h, a C_max of 222.4 ± 12.1 ng·mL^− 1, and an AUC_{0→24&#xa0;h} of 875.6 ± 69.0 ng·h·mL^− 1. In comparison, oral administration resulted in a T_max of 2.0&#xa0;h, a C_max of 146.7 ± 8.2 ng·mL^− 1, and an AUC_{0→24&#xa0;h} of 547.0 ± 39.2 ng·h·mL^− 1. These results indicate that, relative to oral delivery, the biphasic DMNs reached C_max earlier and demonstrated higher bioavailability, as reflected by the increased AUC.</p> Conclusion <p>The PL/GAN-119 DMN system represents a promising strategy for the efficient transdermal delivery of atomoxetine. It enables rapid and enhanced systemic absorption while offering a scalable platform for future clinical translation.</p>