Ezra Cornell was born at Westchester Landing, New York, the oldest of the eleven children of a Quaker family. As a boy, Cornell attended village schools, helped with his father's farm and pottery works, and learned carpentry. He left home at 18, worked as a machinist, and settled in Ithaca, New York, in 1828, where he became manager of the Beebe flour and plaster mills.

When the mills were sold in 1841, Cornell secured the rights to promote a patented plow. This led to a meeting with F. O. J. Smith, congressman from Maine and a partner of Samuel Morse. Smith had contracted with Morse to lay the underground cable for an experimental telegraph line from Baltimore, Maryland, to Washington and was struggling to design a plow that could do the job. Cornell stopped by Smith's office in 1843 and promptly sketched a machine that would dig the trench and lay and bury the cable in one operation. Smith immediately hired Cornell to supervise construction of the line. Cornell's machine was a success, but the underground line was a failure due to faulty insulation. Cornell convinced Morse to string his lines overhead on poles and designed a practical way (variously reported to use broken bottle necks or glass doorknobs) to insulate the wire.

Cornell now made development of the telegraph his career. He built, demonstrated, and promoted numerous lines between major cities in the Northeast and Midwest, included the one over which Morse sent his first message.

By 1855, the ruthless competition among rival telegraph companies led Cornell and other industry leaders to combine their businesses into a single entity, the Western Union Telegraph Company. Cornell was the largest stockholder in the company for the next 15 years, and was a director for the rest of his life.

Western Union made Cornell a wealthy man. He turned to public and educational interests, serving in the state legislature, establishing a model farm near Ithaca and, in 1863, building a free public library for the city. He was a principal founder of Cornell University, which opened in 1868 and was designed, according to Cornell's vision, to offer university-level instruction in technical and agricultural subjects as well as liberal arts. Cornell endowed his namesake school liberally, and his public-land transactions also benefitted the university handsomely. The economic panic of 1873 nearly bankrupted Cornell, however, and he died in Ithaca in 1874.