Pancreatic cancer is one of the deadliest forms of cancer with a very low survival rate. Sialidases are enzymes that play a key role in cancer progression by cleaving sialic acid residues from glycoproteins and glycolipids. The modulation of sialidases in pancreatic cancer has gained considerable attention as a potential therapeutic target for inhibiting tumor growth, invasion, and metastasis. In recent years, research has focused on understanding the mechanisms of sialidase modulation and its impact on tumor biology. Studies have identified sialylated glycans and tumor-associated carbohydrate antigens as important biomarkers for diagnosis and prognosis. Additionally, sialidase modulation has been shown to affect cancer cell signaling pathways, apoptosis, chemoresistance, and immune response. The tumor microenvironment, including extracellular matrix, stromal cells, and immune cells, plays a critical role in pancreatic cancer progression. Sialidase modulation has been shown to impact the tumor microenvironment by influencing the behavior of cancer-associated fibroblasts, tumor-infiltrating lymphocytes, and angiogenesis. Emerging evidence suggests that sialidase modulation may have significant implications for personalized cancer treatment and precision medicine. Furthermore, the identification of novel therapeutic targets and the development of glycan-targeted therapeutics offer exciting prospects for the development of new and effective treatments for pancreatic cancer.