Polyploid giant cancer cells (PGCCs) are increasingly recognized as contributors to tumor progression, therapeutic resistance, and recurrence. One mechanism behind PGCC formation is cell fusion, a process which is regulated by the canonical Wnt/β-catenin signaling pathway during development and tissue regeneration. This pathway modulates physiological cell fusion events such as myogenesis and placental development, as well as pathological cell fusion between cancer cells or between cancer and stromal or immune cells, contributing to PGCC formation. This review examines the multifaceted roles of the Wnt/β-catenin signaling in cell fusion across developmental and cancer contexts, highlighting its involvement in PGCC biology and outlining how therapeutic targeting of this pathway might help modulate cancer progression.