This species is taken by commercial and artisanal longline and gillnet fisheries throughout its range. It is valued for meat, leather, liver oil and fishmeal. The Caribbean reef shark is the most common shark landed in Colombia (accounting for 39% of the longline catch by occurrence), where it is utilized for its fins, oil and jaws (sold for ornamental purposes). In Belize, this species is mainly caught as bycatch on hook-and-line intended for groupers and snappers; the fins are sold to the lucrative Asian market and the meat sold in Belize, Mexico, and Guatemala to make "panades", a tortilla-like confection. A dedicated shark fishery operated in Belize from the mid-1900s to the early 1990s, until catches of all species saw dramatic declines. The flesh of this species may contain high levels of methylmercury and other heavy metals.
Although there are no active reef shark fisheries in the US Pacific, the reef sharks' disappearance could be caused by recreational fishing or illegal shark finning, which, combined, kill 26 million to 73 million sharks each year. Another possible explanation is that the reef sharks are starving. Their food sources, including coral reef fishes, are decreasing in number because of habitat destruction and human exploitation, and could be taking the sharks with them.
On the infrequent occasions when they swim in oceanic waters, grey reef sharks often associate with marine mammals or large pelagic fishes, such as sailfish (Istiophorus platypterus). There is an account of around 25 grey reef sharks following a large pod of bottlenose dolphins (Tursiops sp.), along with 25 silky sharks (C. falciformis) and a single silvertip shark. Rainbow runners (Elagatis bipinnulata) have been observed rubbing against grey reef sharks, using the sharks' rough skin to scrape off parasites.