Fat accumulation in the pancreas, known as nonalcoholic fatty pancreatic disease (NAFPD), is associated with obesity and may lead to prediabetes and Type 2 diabetes. Reducing endoplasmic reticulum stress and enhancing autophagy could offer therapeutic benefits. This study examines the effects of fisetin (FSN) and hydroxychloroquine (HCQ) on NAFPD. Forty-eight Male C57BL/6 J mice were assigned to a standard chow diet (SCD) or a high-fat diet (HFD) for 16 weeks. The HFD group was divided into five subgroups; each group contains eight mice: HFD, HFD + V (vehicle), HFD + FSN, HFD + HCQ, and HFD + FSN + HCQ. FSN was given daily at 80 mg/kg, and HCQ was injected IP at 50 mg/kg twice weekly for more 8 weeks. Insulin resistance was assessed through OGTT and HOMA-IR. Histological analysis of pancreatic tissue was conducted, and the protein and mRNA levels of molecules associated with ER stress and autophagy were assessed using PCR and immunoblotting techniques. FSN and HCQ significantly reduced weight gain, pancreatic adipocyte accumulation, and insulin resistance caused by HFD in obese mice, with the combination of the two compounds producing even more pronounced effects. Additionally, the HFD increased the expression of UPR markers ATF4 and CHOP, a response that was further intensified by HCQ. In contrast, FSN attenuated the UPR by regulating GRP78 levels. Furthermore, the HFD resulted in a significant decrease in the LC3II/LC3I ratio and an accumulation of p62 protein due to reduced p-AMPK levels. Following treatment with FSN, these alterations were reversed, leading to decreased mTOR expression and increased levels of autophagy markers such as ATG5 and Beclin1. Our study reveals that FSN and HCQ effectively combat HFD-induced NAFPD, improving insulin sensitivity and addressing pancreatic fat deposition linked to metabolic syndrome. While HCQ may cause endoplasmic reticulum stress, FSN offers protective effects, supporting their combined use for better treatment outcomes.