[2] According to the United States Census Bureau, the village has a total area of 5.1 square miles (13 km2), all land.

Depew straddles the towns of Lancaster and Cheektowaga and is 11 miles (18 km) east of downtown Buffalo.

Part of the area that Depew currently inhabits was first settled in 1808 by Apollos Hitchcock, just north of Cayuga Creek on the main road that connected Buffalo (spelled as "Buffaloe" at the time) with Lancaster village in what was then Jukdowaageh (now Cheektowaga), which some say meant "land of the crab apple" or "land of fruit and flowers".

The following is from Our County and Its People A Descriptive Work of Erie County New York, edited by Truman C. White: "Depew lies partly in Lancaster and partly in the town of Cheektowaga, but its history is so thoroughly identified with the territory under consideration that it may properly be treated wholly within this chapter.

It was named in honor of Chauncey M. Depew, president of the New York Central and Hudson River Railroad Company, to which it owes its existence.

That great corporation decided upon this site as a permanent location for its shops and auxiliary establishments, and on May 17, 1892, ground was broken.

Before the close of the year 1893 the following establishments had been completed or were well under way: The National Car Wheel Works, the Gould Coupler Company (occupying over six acres), and the Union Car Company (occupying about ten acres).

On July 23, 1894, the village was incorporated, and the first officers elected August 21, were Dr. William Fairbanks, president; John Zurbrick, George Waltz and John Graney, trustees; Anthony Hartung, treasurer; Martin Kiefer, collector; J. N. Oswald, clerk.

The Methodist Episcopal Society was organized July 6, 1894, with E. J. Durbin, B. C. Stoddard and A. W. Southall, trustees; an edifice was erected in 1895.

By February, 1895, the village had a population of 1,814, and by May about 500 dwellings had been erected and few large establishments were in operation employing 2,500 men.

Depew has stations on the New York Central, the D., L. & W., the Erie and the Lehigh Valley Railroads; the latter constructed a branch direct to Tonawanda in 1895-96.

[5] In 1904, Quebec political figure William Clendinneng died in Depew after being hit by a train.

[12] The United States Post Office contains a mural, Beginning of the Day, painted in 1941 by Anne Poor and was listed on the National Register of Historic Places in 1988.

According to the New York State Department of Health, residents of the Village of Depew report instances of psychosis and schizotypal personality disorder 28% higher than the statewide average and incidence of Alzheimer's disease 42% higher than the statewide average, adjusted for population.