Migraine is a chronic neurological disorder that necessitates swift and efficient treatment. Zolmitriptan (ZMT) is a first-line agent with low oral bioavailability and a slow onset of action. Intranasal delivery represents one of the noninvasive routes, directly targeting the nose-to-brain pathway. Therefore, a nano-liposomal system for the co-encapsulation of Zolmitriptan and Ginkgolide B (GB) was developed for efficient intranasal synergistic migraine therapy. The preparation of co-loaded liposomes was performed by thin-film hydration and then optimized by means of DoE. The nanoparticles of the optimal formulation had a mean diameter of 73.13 ± 10.45 nm, high entrapment efficiencies for both ZMT and GB (94.88 ± 2.0% and 95.41 ± 1.3%, respectively) and a biphasic pattern of drug release: a fast burst release of ZMT during the first 2 hours (95.69 ± 4.58%), followed by sustained release of GB within 8 hours (cumulative amount of 98.37 ± 2.87%). The permeation study further demonstrated an increased transport across the olfactory mucosa compared to the control treatments. The formulation was well cytocompatible against the nasal cell line (>80% cell viability) and stable upon storage at refrigerated conditions. In this way, it is emphasized that this new dual-drug co-loaded liposomal system may be of great promise in providing improved migraine management through direct brain delivery, but needs experimentation.