Saint Anthony Cave is an important cultural, religious, and historic site; it was home of Saint Anthony, one of the earliest Christian monks (ca. 251–356 AD). The cave is located in a tectonically-complex karst area developed in partially dolomitic, sandy limestones of latest Paleocene age. Saint Anthony Cave had been described as a phreatic cave in previous research, but the cave lacked a detailed map and its speleogenesis was unclear. New data show the cave is a multi-phased uplifted cave formed primarily under phreatic conditions, with later modification by rising water levels. Deep sources of dissolutionally aggressive solutions likely have been involved. Speleogenesis likely began in Oligocene time associated with the Gulf of Suez Rift evolution and has been erosionally dissected. New, detailed mapping using ArcGIS shows the cave has an area of 22.13 m2 with a length and depth of 17.10 m and 5.33 m, respectively. The cave consists of a northwest–southeast oriented, steeply inclined, fracture controlled, upper-level entrance passage connected to an east–west oriented, fracture controlled, lower-level room with a vertical drop of 2.46 m. Dissolution pockets, cupola-like features, ceiling bell holes, notches, and corrosion tables are present in the cave. Subaerial and subaqueous speleothems moderately decorated the cave with likely Egyptian calcite alabaster. Based on field investigation, regional volcanic and tectonic history, paleoclimates, and other background information, we identify four distinct speleogenetic phases: First, during the late Oligocene, volcanic and extensional tectonic activities fractured the rocks, generated deep-seated acids, and enhanced the rising deep thermal water. Dissolution by other mechanisms such as carbonic/sulfuric acid and mixing dissolution were prevalent. In the early Miocene (Burdigalian), the cave was uplifted. Second, in the late Miocene (about 7.5 Ma), subaerial speleothems were being deposited in the cave under humid climate conditions. Third, post-Miocene, the cave enlarged and modified at and above the water level by likely warm, sulfuric water. Fourth, water levels dropped and speleothems were deposited again during later humid climate conditions.