Migraine is a disabling neurovascular polygenic disorder affecting life quality with escorted socioeconomic encumbrances. Herein, we investigated the consolidated amalgamation of passive lipomer approach alongside active sonophoresis assisted transdermal delivery of zolmitriptan (ZT) using high frequency ultrasound pre-treatment protocol to mitigate migraine attacks. A modified nanoprecipitation technique was utilized to prepare zolmitriptan loaded lipomers (ZTL) adopting 2 factorial design. Three factors were scrutinized namely lipid type, ZT: lipid ratio and ZT: Gantrez® ratio. The prepared systems were characterized regarding particle size, zeta potential, polydispersity index, entrapment efficiency and in-vitro release studies. The best achieved ZTL system was evaluated for ZT- Gantrez® intermolecular interactions, drug crystallinity, morphology, ex-vivo permeation and histopathological examination. Finally, a comparative in-vivo biodistribution study through radiotracking technique using Technetium-99m was adopted. L2 was the best-achieved ZTL system with respect to spherical particle size (390.7 nm), zeta-potential (-30.8 mV), PDI (0.2), entrapment efficiency (86.2%), controlled release profile, flux (147.13 μg/cm/hr) and enhancement ratio (5.67). Histopathological studies proved the safety of L2 system upon application on skin. L2 revealed higher brain C (12.21 %ID/g), prolonged brain MRT (8.67 hr), prolonged brain .23 hr), significantly high relative bioavailability (2929.36%) and similar brain T (0.5 hr) compared to I.V. route with higher brain/blood ratio. Thus, sonophoresis assisted transdermal delivery of ZTL offers a propitious alterative to alleviate migraine symptoms.