He took classes at The College of Wooster, before transferring to The Ohio State University. He was a member of the Delta Upsilon Fraternity. Eye problems forced him to withdraw, and he took a job as foreman of a telephone line crew. At first, the termination of his studies caused him to be depressed. Then he found ways to apply his electrical engineering skills on the job, and his spirits revived. He also met his Future wife, Olive Williams. When his eye condition improved, he was able to return to his studies and graduated from OSU in 1904 with an electrical engineering degree.

Kettering married Olive Williams of Ashland, Ohio, on August 1, 1905. Their only child, Eugene Williams Kettering, was born on April 20, 1908. Eugene W. Kettering joined Winton Engine in 1930, which was acquired by General Motors and was eventually incorporated into the General Motors Electro-Motive Division (EMD). The younger Kettering became a central figure in the development of the EMD 567 and the Detroit Diesel 6-71, serving at EMD until his retirement in 1960.

Kettering was hired directly out of school to head up the research laboratory at National Cash Register (later known as NCR Corporation). Kettering invented an easy credit approval system, a precursor to today's credit cards, and the electric cash register in 1906, which made ringing up sales physically much easier for sales clerks. Kettering distinguished himself as a practical Inventor. As he said, "I didn't hang around much with other inventors and the executive fellows. I lived with the sales gang. They had some real notion of what people wanted." During his five years at NCR, from 1904 to 1909, Kettering secured 23 patents for NCR. He attributed his success to a good amount of luck but added, "I notice the harder I work, the luckier I get."

Beginning in 1907, his NCR colleague Edward A. Deeds convinced Kettering to develop improvements for the automobile. He told Kettering, "There is a river of gold running past us," implying that, with their know-how, all they needed to do was dip into it. Deeds and Kettering invited other NCR Engineers, including Harold E. Talbott, to join them nights and weekends in their tinkering at Deeds's barn. They became known as the "Barn Gang," and Kettering was their leader. Boss Ket, they called him. They set their first task as improving ignition, replacing the magneto. In 1909, Kettering resigned from NCR to work full-time on Automotive developments. The Barn Gang incorporated as Dayton Engineering Laboratories Company, or Delco

Early automobiles required a hand crank for starting. Occasionally, when the spark lever was not properly set, the hand crank kicked back, causing serious injury: a broken wrist, arm, or shoulder. On a winter night in 1908, the result was much worse.

Leland's Engineers were able to build an electric self-starter, but the device was not small enough to be practical. He called Charles Kettering. The Engineers at Delco worked around the clock to get the job done by the February 1911 deadline. Kettering later described their work thus: They didn't have a job so much as the job had them.

Kettering held 186 U.S. patents. He invented the all-electric starting, ignition, and lighting system for automobiles. Electric starters replaced crank (manual) starting of automobiles. First incorporated in the 1912 Cadillac, all-electric starting aided in the growth of the US auto industry by making the automobile easy for anyone to start. Other patents included a portable lighting system and an incubator for premature infants. His engine-driven generator was combined with storage batteries to form a "Delco Plant", providing an electrical power for farmsteads and other locations far from the electrical power grid.

Kettering's self-starter won a Dewar Trophy in 1913.

Charles Kettering built a house, "Ridgeleigh Terrace", in 1914. According to local sources, this house was the first in the United States to have electric air conditioning. Ridgeleigh Terrace was the home of his son, Eugene Kettering, until his death. Eugene's wife, Virginia Kettering, lived in the house for many years, restoring and redecorating it. In the late 1990s, the house was seriously damaged in a fire, but it was rebuilt according to the original blueprints.

In 1918 Kettering designed the "aerial torpedo", nicknamed the Kettering Bug. The 300 lb papier-mache missile had 12 foot cardboard wings, and a 40 hp engine. It could carry 300 lbs of high explosives at 50 mph, and cost $400. The "Bug" is considered the first aerial missile, and lessons learned from the "Bug" led to development of the first guided missiles, as well as radio-controlled drones.

Kettering's research in fuel was based on his belief that oil would be in short supply and additives would allow more efficient engines with higher compression. His "high percentage" solution was to mix ethanol with gasoline, while his "low percentage solution" looked for additives that would be added in small quantities to increase what later would be called the octane rating of gasoline. Thomas Midgley Jr. and Kettering identified tetraethyllead (TEL) in December 1921 as an additive that would eliminate engine knocking at a dilution of one thousand to one. While use of ethanol could not be patented, TEL's use as an additive could. Kettering and Midgley secured its patent and proceeded to promote the use of TEL as an additive instead of other options. Kettering became the first President of the newly founded Ethyl Corporation that started to produce TEL in 1923. One year later, he hired Robert A. Kehoe as the medical expert to proclaim that leaded gasoline was safe for humans. That its use was an ecological disaster leading to a global lead contamination was not acknowledged until many decades later.

His inventions, especially the electric automobile starter, made him wealthy. In 1945, he helped found what became the Memorial Sloan Kettering Cancer Center, based on the premise that American industrial research techniques could be applied to cancer research.. His son and daughter-in-law, Eugene and Virginia, created Kettering Medical Center in Ohio, as a tribute to Charles Kettering's life and his work in Health care research.

The city of Kettering, Ohio, a suburb of Dayton, was named after him when it was incorporated in 1955.

Kettering died on November 25, 1958. After his death, his body lay in honor at the Engineers Club and then was interred in the mausoleum at Woodland Cemetery, Dayton, Ohio.

Kettering and colleagues' development of leaded gasoline ultimately caused the release of large quantities of lead into the atmosphere as a result of the combustion of leaded gasoline all over the world. Due to the neurotoxic effects of lead, leaded gasoline has been widely banned since the late 1990s. The development of Freon using CFCs has been implicated in the depletion of the ozone layer. But during the first half of the twentieth century, most people, including Kettering and his colleagues, did not appreciate or fully understand the environmental degradation potential of their work. They believed, although perhaps obstinately, that the lead concerns were negligible. They were not aware of the ozone layer depletion at the time. It took decades for the lessons to be learned.

In 1998, GMI Engineering and Management Institute (formerly General Motors Institute), of Flint, Michigan, changed its name to Kettering University in honor of Kettering. His ideals, prowess, and belief in co-operative education continue there. Kettering is also remembered through the Memorial Sloan-Kettering Cancer Center, a cancer research and treatment center in New York City, and through the Kettering Health Network, which includes several hospitals and medical center campuses as well as Kettering College in Kettering, Ohio.