Conventional oral therapy of lymphatic filariasis drugs is only effective to kill microfilariae in the bloodstream, but is often ineffective to kill adult filarial (macrofilariae) in the complex anatomy of the lymphatic system. The encapsulation of drugs into lipid-based nanoparticles with sizes of <100nm, and administration intradermally, could be used to enhance lymphatic uptake. Therefore, we developed an innovative approach, using solid lipid nanoparticles (SLNs) and dissolving microneedles (MNs) to deliver antifilariasis drugs, namely doxycycline, diethylcarbamazine and albendazole, intradermally. The SLNs were prepared from Geleol® and Tween®80 as a lipid matrix and stabilizer, respectively. The formulations were optimized using a central composite design, producing SLNs with sizes of <100nm. Drug release was sustained over 48h from SLNs, compared to pure drugs. The SLNs were then incorporated into a polymeric hydrogel which was casted to form SLNs-loaded MNs. SLNs-loaded MNs exhibited sufficient mechanical and insertion properties. Importantly, dermatokinetic studies showed that>40% of drugs were retained in the dermis of excised neonatal porcine skin up to 24h post-MN application, indicating the high possibility of the SLNs to be taken by the lymphatic system. In in vivo studies, the maximal lymph concentrations of the three drugs in rat, achieved following intradermal delivery, ranged between 4- and 7-fold higher than that recorded after oral administration. Additionally, compared to oral administration, despite the lower plasma Cmax and organ-distribution, the AUC and relative bioavailability of the three drugs in rat plasma was also higher using our delivery approach. Accordingly, this delivery approach could maximize the drugs concentrations in the lymph system without essentially increasing their plasma concentrations. This could potentially deliver the drugs efficiently to the bloodstream, where the microfilariae reside, while also targeting drug to the lymph nodes, where filarial nematodes reside in infected patients, leading to an effective therapy for lymphatic filariasis.