Background: Acute pancreatitis is a significant global disease. This study investigated the phytochemical composition and potential protective effects of Equisetum arvense L. (horsetail) ethanol extract and Olea europaea L. (olive leaves) aqueous extract against metronidazole (MTZ)-induced pancreatic damage in rats. Materials and Methods: Rats were randomly divided into six groups: Group I (control) received saline; Group II (Metronidazole) received only MTZ (400 mg/kg). Group III (Equisetum arvense group) received E. arvense 100 mg/kg. Group IV (Olea europaea) received 400 mg/kg of O. europaea. Group V (MTZ + E. arvense) received both MTZ (400 mg/kg) and E. arvense (100 mg/kg). Group VI (MTZ + O. europaea) received MTZ (400 mg/kg) and O. europaea (400 mg/kg). All treatments were delivered daily via the oral route. After 60 days, serum amylase, lipase, protease, and glucose levels, oxidative parameters “malondialdehyde (MDA), catalase (CAT), mRNA relative expression of pancreatic Pik3ca (phosphatidylinosi-tol-4,5-bisphosphate 3-kinase, catalytic subunit alpha), AKT (AKT Serine/Threonine Kinase 1), Nrf-2 (Nuclear factor, erythroid 2-like 2), TNFα (tumor necrosis factor alpha), and IL-1β (interleukin-1 beta genes, an apoptotic marker “caspase-3,” and histopathological changes were estimated. Results: HPLC analysis revealed that horsetail extract contained caffeic acid, catechin, rutin, and kaempferol, while olive leaf extract was dominated by oleuropein. MTZ administration significantly elevated serum levels of pancreatic enzymes (lipase, amylase, and protease) and glucose and increased oxidative stress markers, such as MDA, while reducing catalase (CAT) activity. Co-treatment with MTZ and horsetail, or MTZ and olive extracts, mitigated these effects, especially horsetail, which restored CAT levels and reduced MDA concentrations. qPCR analysis showed MTZ upregulated inflammatory genes (TNFα, IL-1β) and downregulated antioxidant and survival-related genes (Pik3ca, AKT, Nrf-2). Horsetail co-treatment significantly reversed these gene expression patterns. Histopathological and immunohistochemical analyses confirmed MTZ-induced pancreatic tissue degeneration and increased cleaved caspase-3 expression, both of which were notably alleviated by horsetail extract. Conclusions: These findings highlight the superior protective efficacy of Equisetum arvense over Olea europaea in ameliorating MTZ-induced pancreatic toxicity, potentially through anti-inflammatory, antioxidant, and anti-apoptotic mechanisms.