Many businesses failed in the panics of the 1890s, including the street railway company owned by Seiberling's father. In 1898, he was jobless, nearing 40, with a wife and three children. Seiberling learned of the availability of an old strawboard factory in East Akron, which he purchased, together with the seven acres it stood on, for $13,500. He borrowed $3,500 for a down payment from a brother-in-law, Lucius C. Miles,, who would become the company's third president in 1900. In a few days he had decided what business he would go into, picked a name, and was selling stock. The business would be rubber; the company would be named for Charles Goodyear, the discoverer of vulcanization, who had died penniless almost 40 years before.
In 1899, Raymond C. Penfield, another brother-in-law, became the second president of Goodyear Tire and Rubber Company. In 1906, Seiberling became the fourth president of the company, a position he held until 1921. He was known as the "little Napoleon" of the rubber industry because of his small stature and his unremitting determination to succeed. He played a leading role in developing Akron, Ohio from a small town into the rubber center of the world.
1921, Goodyear was refinanced and reorganized, and Seiberling and his brother Charles resigned from the company. He then began the Seiberling Rubber Company in Barberton, Ohio.
During his lifetime, Seiberling became famous for his fair treatment of workers.
Seiberling donated millions of dollars to charitable causes in his community. He served on the board of trustees of Buchtel College and assisted the college in becoming the University of Akron. .
In 1985, Seiberling was inducted into the Tire Industry Hall of Fame.