Neuropathic pain (NP) is a debilitating chronic condition frequently refractory to available therapies, while the therapeutic potential of cannabidiol (CBD) is limited by its unfavorable physicochemical and pharmacokinetic properties. This study investigated whether incorporation of CBD into a lipid-based microemulsion (LS-CBD) could improve its antinociceptive profile in a murine model of NP, and explored potential molecular mechanisms and safety. LS-CBD was prepared by a high-energy emulsification method and exhibited nanometric droplet size, narrow size distribution, high entrapment efficiency (96.8 ± 0.7%), and physicochemical stability over 60 days. Male C57BL/6 mice subjected to partial sciatic nerve ligation were evaluated for mechanical and thermal nociception following acute and repeated oral administration of CBD and LS-CBD (25, 50, and 75 mg/kg). Compared with free CBD, LS-CBD prolonged the duration of thermal antinociception (1–8 h vs. 2 h) and produced a significantly greater global antinociceptive effect. Peak antinociception did not differ between formulations (50.0 ± 14.9% vs. 53.2 ± 25.5%), indicating that nanoencapsulation prolonged the response rather than increasing its magnitude. Under repeated administration, LS-CBD produced significant mechanical antinociceptive activity on every day of the seven-day treatment period, while both formulations produced comparable and sustained thermal antinociception without evidence of tolerance development. At the molecular level, both CBD and LS-CBD increased Sod1 and Cat transcripts relative to naive animals, and reduced Nos2 and Gfap transcripts relative to neuropathic controls, in the dorsal root ganglia, suggesting attenuation of nitrosative stress and satellite glial cell activation. Neither treatment induced hematological, biochemical, or body weight alterations following repeated administration. These findings support lipid-based nanoencapsulation as a strategy to extend the duration of CBD antinociception after oral administration.