Hull was born in Olympus, Pickett County, Tennessee, third of the five sons of william Paschal Hull (1840–1923) and Mary Elizabeth Riley Hull (1841–1903). His brothers were named Orestes (1868), Sanadius (1870), Wyoming (1875), and Roy (1881).

Hull attended college from 1889 until 1890. He gave his first speech at the age of 16. At the age of 19, Hull became the elected chairman of the Clay County Democratic Party. In 1891, he graduated from Cumberland School of Law at Cumberland University and was admitted to the bar. He served in the Tennessee House of Representatives from 1893 to 1897.

From 1903 to 1907, Hull served as a local judge; later he was elected to the United States House of Representatives where he served 11 terms (1907–1921 and 1923–1931) totaling 22 years. As a member of the powerful Ways and Means committee, he fought for low tariffs and claimed authorship of the federal income tax laws of 1913 and 1916 and the inheritance tax of 1916. After his defeat in the congressional election of 1920, he served as chairman of the Democratic National Committee. He was one of several candidates for President at the 1928 Democratic National Convention, which ultimately chose Al Smith as nominee. Hull was influential in advising Albert Gore, Sr., then a state legislator, to run for the U.S. Congress in 1938.

Hull served eleven terms in the United States House of Representatives (1907–1921 and 1923–1931) and authored the federal income tax laws of 1913 and 1916 and the inheritance tax of 1916. After an electoral defeat in 1920, Hull served as chairman of the Democratic National Committee. He was returned to the House in 1922 and was then elected to the Senate in 1930, but resigned upon being named Secretary of State in 1933. Hull recorded thirty years of combined Service in the House and the Senate.

At the age of 45, in 1917 he married a widow Rose Frances (Witz) Whitney Hull (1875–1954), of an Austrian Jewish family of Staunton, Virginia; the couple had no children. Mrs. Hull died at age 79, in Washington, D.C., in 1954.

Hull was elected to the Senate in 1930. In 1933, Roosevelt named him Secretary of State and appointed him to lead the American delegation to the London Economic Conference. Hull strove to enlarge foreign trade and lower tariffs. In 1943, Hull served as United States delegate to the Moscow Conference.

In a speech in 1937, Mayor LaGuardia of New York said that brown-shirted Nazis ought to be featured as the "climax" of a chamber of horrors in the upcoming World's Fair. The Nazi government organ, the Angriff, called the Mayor a "Jewish Ruffian" saying he had been bribed by Jewish and Communistic agents and was a Criminal disguised as an officeholder. In the ensuing exchanges, Hull sent a letter of regret to Berlin for intemperate comments on both sides, while also explaining the principle of freedom of speech. As the response of Nazi propaganda organs rose in pitch, to include characterizing American women as "prostitutes", Hull sent a letter of protest to Berlin, which elicited an "explanation" but no apology.

In 1938, Hull engaged in a famous dialog with Mexican Foreign Minister Eduardo Hay concerning the failure of Mexico to compensate Americans who lost farmlands during the Agrarian reforms of the late 1920s. He insisted that compensation must be "prompt, adequate and effective". Though the Mexican Constitution guaranteed compensation for expropriation or nationalization, nothing had yet been paid. While Hay admitted Mexico's responsibility, he replied that there is "no rule universally accepted in theory nor carried out in practice which makes obligatory the payment of immediate compensation..." The so-called "Hull formula" has been adopted in many treaties concerning international investment, but is still controversial, especially in Latin American countries, which historically have subscribed to the Calvo Doctrine, which among other things, suggests that compensation is to be decided by the host country and that as long as there is equality between nationals and foreigners and no discrimination, there cannot be any claim in international law. The tension between the Hull formula and the Calvo Doctrine is still of importance today in the law of international investment.

In 1939, Hull advised President Roosevelt to reject the SS St. Louis, a German ocean liner carrying 936 Jews seeking asylum from Germany. Hull's decision sent the Jews back to Europe on the eve of the Nazi Holocaust. Many of the passengers were ultimately murdered by the Nazis.

In September 1940, First Lady Eleanor Roosevelt maneuvered with another State Department official to bypass Hull's refusal to allow Jewish refugees aboard a Portuguese ship, the SS Quanza, to receive visas to enter the U.S. Through Mrs. Roosevelt's efforts, the Jewish refugees disembarked on September 11, 1940, in Virginia. In a similar incident, American Jews sought to raise money to prevent the mass murder of Romanian Jews. However, "In wartime, in order to send money out of the United States, two government agencies had to sign a simple release- the Treasury Department under Henry Morgenthau and the State Department under Secretary Cordell Hull. Morgenthau signed immediately. The State Department delayed, delayed, and delayed, as more Jews were dying in the Transnistria camps."

When the Free French Forces of Charles de Gaulle occupied the islands of Saint-Pierre and Miquelon south of Newfoundland in December 1941, Hull lodged a very strong protest and even went as far as referring to the Gaullist naval forces as "the so-called Free French". His request to have the Vichy governor reinstated was met with strong criticism in the American press. The islands remained under the Free French movement until the end of World War II.

Hull chaired the Advisory Committee on Postwar Foreign Policy, created in February 1942.

Hull resigned on November 30, 1944 because of failing health as the longest-serving Secretary of State, having served 11 years, nine months in that post. Roosevelt described Hull upon his departure as "the one person in all the world who has done his most to make this great plan for peace (the United Nations) an effective fact". The Norwegian Nobel Committee honored Hull with the Nobel Peace Prize in 1945 in recognition of his efforts for peace and understanding in the Western Hemisphere, his trade agreements, and his work to establish the United Nations.

Hull was the underlying force and Architect in the creation of the United Nations, as recognized by the 1945 Nobel Prize for Peace, an honor for which Franklin D. Roosevelt nominated him. During World War II, Hull and Roosevelt had worked toward the development of a world organization to prevent a third World War. Hull and his staff drafted the "Charter of the United Nations" in mid-1943.

He died on July 23, 1955, at age 83, at his home in Washington, D.C., after a lifelong struggle with familial remitting-relapsing sarcoidosis (often confused with tuberculosis). He is buried in the vault of the Chapel of St. Joseph of Arimathea in the Washington National Cathedral.

The Shoreline School District in Shoreline, Washington, formerly had a Cordell Hull Middle School; it was renamed in the mid-1990s to Meridian Park Elementary, after a renovation.

In 1940, Jewish representatives in the USA lodged an official complaint against the discriminatory policies the State Department was using against the Jews; the results were fatal: The Secretary of State [Cordell Hull] gave strict orders to every USA consulate worldwide forbidding the issuing of visas to Jews ... At the same time a Jewish congressman petitioned the President [FDR], requesting his permission to allow twenty thousand Jewish children from Europe to enter the USA. The President totally ignored this petition as well as its sender. (The Australian Jewish News, 6 May 1994, p. 9 (translated from the Yiddish).

Cordell Hull Birthplace State Park, near Byrdstown, Tennessee, was established in 1997 to preserve Hull's birthplace and various personal effects Hull had donated to the citizens of Pickett County, including his Nobel Peace Prize.

During the Spanish–American War, Hull served in Cuba as a captain in the Fourth Regiment of the Tennessee Volunteer Infantry.