Mayhew is located at 33°29′05″N88°38′04″W / 33.48472°N 88.63444°W / 33.48472; -88.63444 west of Columbus, north of Artesia, east of Starkville and south of West Point. According to the United States Geological Survey, a variant name is Mayhew Station. Mayhew Station was the original name given to this community when it was moved from its original site (near Muldrow, Mississippi) to alongside the tracks of the newly built Mobile and Ohio Railroad (later Gulf, Mobile & Ohio) in the very early 1850s. The original location of the town of Mayhew is now referred to as Old Mayhew, but only a cemetery exists there today. Mayhew held the distinction for most of the 20th century as being home to Stover Apiaries, the world's largest queen bee apiary, which shipped queen bees to beekeepers worldwide.
Mayhew is also referred to as Mayhew Junction, or more commonly as "The Crossroads" by area residents, a reference to when US Highways 82 and 45 crossed as at-grade two-lane highways. Before the construction of the new US 82 and the expansion of US 45 to four lanes, the intersection of the original highways was a four way stop. Several bars and service stations lined the four sides of the original intersection, and were torn down when the new expressways were built over a period of several years between 1975 and 1995.