Ellender was born in the town of Montegut in Terrebonne Parish. He attended public and private schools and graduated from the Catholic St. Aloysius College in New Orleans, now Brother Martin High School in 1909, when he was only nineteen. He studied law at Tulane University in New Orleans. He was admitted to the bar in 1913 and launched his practice in Houma when he was twenty-three.
Ellender was a delegate to the Louisiana constitutional convention in 1921. The constitution produced by that body was retired in 1974, two years after Ellender's death. He served in the Louisiana House of Representatives from 1924-1936. He was floor leader from 1928-1932 and Speaker from 1932-1936, when he was elected to the U.S. Senate. He took the seat held by Long and slated for the Democratic nominee, Oscar Kelly Allen, Sr., of Winnfield, the seat of the Longs' home parish of Winn. Allen had won the Democratic nomination by a plurality exceeding 200,000 votes, but he died shortly thereafter. His passing paved the way for Ellender's election. Lorris M. Wimberly of Arcadia in Bienville Parish, meanwhile, succeeded Ellender as House Speaker. Wimberly was the choice of Governor Richard Webster Leche and thereafter Lieutenant Governor Earl Kemp Long, who succeeded Leche to the governorship.
Ellender was President pro tempore of the U.S. Senate from 1971-1972. He also served as the chairman of the Senate Agriculture Committee from 1951 to 1953 and 1955 to 1971, through which capacity he was a strong defender of sugar cane interests. He was also chairman of the Senate Appropriations Committee from 1971 until his death.
Ellender, along with liberal Republican Ralph Flanders of Vermont, was a vociferous opponent of McCarthyism and attacked the methods of investigating communism used by Republican Senator Joseph Raymond McCarthy of Wisconsin.
Ellender was steadfastly loyal to all Democratic presidential nominees and refused to support then Governor Strom Thurmond of South Carolina for president in 1948, when Thurmond, the States Rights Party nominee was also the official Democratic nominee in Louisiana and three other southern states. Ellender supported Harry Truman, whose name was placed on the ballot only after Governor Earl Kemp Long called a special session of the legislature to place the president's name on the ballot. "As a Democratic nominee, I am pledged to support the candidate of my party, and that I will do," declared Ellender, though he could have argued that Thurmond, not Truman, was technically the "Democratic nominee" in Louisiana.
Ellender crushed Reese's hopes of making a respectable showing: he polled 432,228 (79.8 percent) to Reese's 109,698 (20.2 percent). Reese's best performance was in two parishes which voted for Richard M. Nixon, La Salle Parish (Jena) and Ouachita Parish (Monroe), where he drew less than a third of the ballots -- 31.3 percent in each. In Caddo Parish (Shreveport), Reese finished with 30 percent. Reese was only the third Republican since the Seventeenth Amendment was ratified even to seek a U.S. Senate seat from Louisiana. Ellender ran 24,889 votes ahead of the John F. Kennedy-Lyndon Johnson ticket, but 265,965 votes cast in the presidential race ignored the Senate contest, a phenomenon that would later be called an "undervote."
In 1966, Ellender disposed of two weak primary opponents, including the liberal State Senator J.D. DeBlieux (pronounced "W") of Baton Rouge (1912-2005) and the conservative businessman Troyce Guice (1932-2008), a native of St. Joseph, the seat of Tensas Parish, who then resided in Ferriday, and later in Natchez, Mississippi. The Republicans did not field a candidate against Ellender that year.
Ellender cultivated good relationships with the media, whose coverage of his tenure helped him to fend off serious competition. One of his newspaper favorites was Adras LaBorde, longtime managing editor of Alexandria Daily Town Talk. The two "Cajuns" even shared fish stories on many occasions.
Ellender's immediate successor was Elaine Schwartzburg Edwards, first wife of Governor Edwards, who filled his seat from July to November 1972.
In 1994, Ellender was inducted posthumously into the Louisiana Political Museum and Hall of Fame in Winnfield.