Predation is an evolutionary force shaping sea floor communities, with the record of drilling predation being particularly useful to study predatory behavior on short and long timescales. Most predatory drill holes are caused by gastropods, but octopods within Octopodoidea also produce characteristic drill holes, yet remain severely understudied in deep time. Consequently, studies comparing octopodoid versus gastropod drill holes from the same prey group are exceedingly rare. Cypraeid gastropod (cowries) are commonly drilled by octopodoids today, but nothing is known about drill holes produced by octopodoids and gastropod in fossil cypraeids. We studied 2406 Plio-Pleistocene fossil cowries from southern Florida, USA. Drilling by octopodoids was common (13.4% of specimens), whereas gastropod drill holes were rare (0.2%). There is strong site selectivity: most octopodoid drill holes are found in the ventral-left-posterior and ventral-left-middle shell regions. These parts are not the thinnest region of the shell, but represent the location where the columellar muscle anchors the soft tissue to the shell interior. We suggest that the octopodoids sought to paralyze and relax this muscle via the drill hole to minimize the time to consumption. Specimens with multiple octopodoid drill holes (24.1% of drilled specimens) have a higher proportion of drill holes located outside the ventral-left-posterior and ventral-left-middle regions. Thus, drilling outside these regions appears less effective. The few gastropod drill holes occur on the dorsal side. A meta-analysis shows that octopodoids produce significantly more drill holes per drilled molluscan shell than do gastropod drillers. We found mixed evidence for size selectivity: whereas the size of drilled specimens does not significantly differ from non-drilled specimens, drill-hole size is significantly larger in larger cowries, which may imply they were drilled by larger octopodoid individuals. We suggest that the molluscan fossil record should be leveraged to further study the evolution of octopodoid predation and behavior.