Diclofenac sodium (DIC) is a pain reliever and anti-nociceptive medication. Significant limitations of DIC treatment stem from its adverse effects. This study investigates the feasibility of using natural Lycopodium clavatum sporopollenin (LCS) microcapsules loaded with DIC to mitigate the hepatotoxicity associated with DIC treatment. In addition, LCS microcapsules were tracked in the blood, stomach, small intestine, and feces of rats to demonstrate their morphological integrity and uptake behavior. Four groups (6 per group) of adult male albino rats were administered normal saline (control), empty LCS (30 mg kg-1), plain DIC (10 mg kg-1), and DIC-loaded LCS (40 mg kg-1) orally for seven consecutive days. The first comprehensive histological examination of the rat stomach demonstrated the robustness and bioadhesion ability of LCS under severe conditions. The findings suggested that these versatile microcapsules are unlikely to be digested in the gastrointestinal tract (GIT). The administration of DIC-loaded LCS was found to play a potential protective role in regulating DIC-induced substantially increased serum levels of transaminases, alkaline phosphatase, total bilirubin, and pro-inflammatory cytokines. In addition, DIC-loaded LCS restored the antioxidant enzymes, DNA damage, and liver histological architecture abnormalities caused by DIC. Microencapsulation of DIC into pollen-derived biomaterials could be employed as an efficient platform with enough safety coverage on rat liver, pending further clinical studies.