Cannabidiol (CBD) has been recognized for its numerous therapeutic benefits, such as neuroprotection, anti-inflammatory effects, and cardioprotection. However, CBD has some limitations, including unpredictable pharmacokinetics and low oral bioavailability. To overcome the challenges associated with CBD delivery, we employed Design of Experiments (DoE), lipid carriers, and 3D printing techniques to optimize and develop buccal film loaded with CBD-NLCs. Three-factor Box-Behnken Design was carried out to optimise the NLCs and analyse the effect of independent factors on dependent factors. The emulsification-ultrasonication technique was used to prepare the NLCs. A pressure-assisted micro-syringe printing technique was used to produce the films. The produced films were studied for physicochemical, and mechanical properties, release profiles, and predicted in vivo performance. The observed particle size of the NLCs ranged from 12.17 to 84.91 nm whereas the PDI varied from 0.099 to 0.298. Lipid and sonication time positively affected the particle size whereas the surfactant concentration was inversely related. CBD was incorporated into the optimal formulation and the observed particle size, PDI, and zeta potential for the CBD-NLCs were 94.2 ± 0.47 nm, 0.11 ± 0.01 and - 11.8 ± 0.52 mV. Hydroxyethyl cellulose (HEC)-based gel containing the CBD-NLCs was prepared and used as a feed for 3D printing. The CBD-NLCs film demonstrated a slow and sustained in vitro release profile (84. 11 ± 7.02% in 6 h). The predicted AUC h, C, and T were 201.5 µg·h/L, 0.74 µg/L, and 1.28 h for a film with 0.4 mg of CBD, respectively. The finding demonstrates that a buccal film of CBD-NLCs can be fabricated using 3D printing.