Berberine hydrochloride (BH), a naturally occurring alkaloid having pleiotropic biological effects, is characterized by high water solubility, poor bioavailability, and a brief half-life. The objective of this study was to develop a liposomal formulation of BH that is more accessible and to ascertain whether its intraperitoneal administration might mitigate pancreatic tissue damage in rats that have been induced by alloxan. Rats were divided into four groups: control, alloxan, metformin, and BH-liposomes (BH-Lip). Measurements of blood glucose, insulin, pancreatic antioxidant state, and pro-inflammatory mediators were used to assess the severity of pancreatic injury in rats among all groups. According to the results, BH-Lip reduced the extent of alloxan-induced pancreatic tissue damage in rats, as demonstrated by improved HOMA-IR and HOMA-β scores, insulin, total pancreatic antioxidant capacity, and lower blood glucose levels. Furthermore, BH-Lip boosted the antioxidant transcription factor Nrf2 and downregulated the mRNA expression of pancreatic pro-inflammatory mediators, such as NF-κB and NLRP3. Moreover, immuno-histochemical labeling revealed that BH-Lip inhibited the protein transcription of caspase-3 and TNF-α in the pancreatic tissues of alloxan-treated rats. These findings provide BH-Lip as a safe substitute for traditional antidiabetics by reducing pancreatic tissue damage caused by alloxan via targeting the Nrf2/NF-κB pathway.