Thinly sliced fried slabs on white toast became widespread on menus in St. Louis, Missouri, after the rise of the city's stockyards in the late 1880s, although demand there has so dwindled that only a handful of restaurants still offer them. They remain popular in the Ohio River valley, where they are served heavily battered on hamburger buns. In Evansville, Indiana, they are still offered at several "mom and pop" eateries, specifically the Hilltop Inn, and remain a favorite dish, featured at the city's annual West Side Nut Club Fall Festival. Kissner's, a traditional workman's taproom in Defiance, Ohio, has offered a brain sandwich since 1928.
Brains from cows over 30 months old at slaughter are no longer permitted to be sold for human consumption in the United States. Some restaurants have taken to serving pigs' brains instead of cows' brains due to concerns regarding bovine spongiform encephalopathy, commonly known as "mad cow disease". Because pigs' brains are substantially smaller than cows' brains, the amount of preparation required for each sandwich increases. Each brain must be cleaned before being sliced and pigs' brains produce fewer slices.