Non-steroidal anti-inflammatory drugs (NSAIDs) represent the foundation of pain management caused by inflammatory disorders. Nevertheless, their oral administration induces several side effects exemplified by gastric ulceration, thus, delivering NSAIDs via skin has become an attractive alternative. Herein, microemulsion-based hydrogel (MBH), proliposomal, and cubosomal gels were fabricated, loaded with diclofenac, and physicochemically characterized. The size, charge, surface morphology, and the state of diclofenac within the reconstituted gels were also addressed. The ex-vivo permeation study using Franz cells was performed via the rat abdominal skin. The formulations were assessed in-vivo on mice skin for their irritation effect and their anti-nociceptive efficacy through tail-flick test. Biosafety study of the optimal gel was also pointed out. The gels and their dispersion forms displayed accepted physicochemical properties. Diclofenac was released in a prolonged manner from the prepared gels. MBH revealed a significantly higher skin permeation and the foremost results regarding in-vivo assessment where no skin irritation or altered histopathological features were observed. MBH further induced a significant anti-nociceptive effect during the tail-flick test with a lower tendency to evoke systemic toxicity. Therefore, limonene-containing microemulsion hydrogel is a promising lipid-based vehicle to treat pain with superior safety and therapeutic efficacy.