Born in Orient, Iowa, Vance spent most of his childhood in Nebraska. He played semipro baseball there, then signed on with a minor league baseball team out of Red Cloud, Nebraska, a member of the Nebraska State League, in 1912. After pitching for two other Nebraska State League teams in 1913 (Superior) and 1914 (Hastings Giants), Vance made a brief major league debut with the Pittsburgh Pirates in 1915 and appeared with the New York Yankees that year as well. However, it took several years before he established himself as a major league player.

Vance was discovered to have an arm injury in 1916 and was given medical treatment. He continued to work on his pitching in the minor leagues, appearing with teams in Columbus, Ohio; Toledo, Ohio; Memphis, Tennessee; Rochester, New York; and Sacramento, California. He only reappeared in the major leagues once for the Yankees, pitching two games in 1918. Vance said he was suddenly able to throw hard again in 1921 while pitching for the New Orleans Pelicans of the Southern Association: he struck out 163 batters and finished the season with a 21–11 win-loss record. The Pelicans sold his contract to the Brooklyn Robins in 1922. The Robins wanted to acquire catcher Hank DeBerry, but the Pelicans refused to complete the deal unless Vance was included in the transaction.

Vance and DeBerry formed a successful battery during their tenure with Brooklyn. In 1922, Vance produced an 18–12 record with a 3.70 earned run average (ERA) and a league-leading 134 strikeouts. His best individual season came in 1924, when he led the National League in wins (28), strikeouts (262) and ERA (2.16) (see Triple Crown) en route to winning the National League Most Valuable Player Award. He set the then-National League record for strikeouts in a nine-inning game when he fanned 15 Chicago Cubs in a game on August 23, 1924. (He struck-out 17 batters in a 10-inning game in 1925.)

On September 24, 1924, Vance struck out three batters on nine pitches in the second inning of a 6–5 win over the Chicago Cubs. Vance became the fifth National League pitcher and the seventh pitcher in MLB history to accomplish the nine-strike/three-strikeout half-inning. He finished the season with 262 strikeouts, more than any two National League pitchers combined (Burleigh Grimes with 135 and Dolf Luque with 86 were second and third respectively). That season, Vance had one out of every 13 strikeouts in the entire National League. Vance pitched a no-hitter on September 13, 1925 against the Phillies, winning 10–1.

Vance’s play began to decline in the early 1930s and he bounced to the St. Louis Cardinals (becoming a member of the team known as the Gashouse Gang), Cincinnati Reds and back to the Dodgers. On September 12, 1934, Vance hit his seventh and final major league home run at 43 years and 6 months, the 2nd oldest pitcher to do so to this day. However, just a week later commenting for a newspaper article, Vance said that he did not recommend baseball as a career to young men. He pointed out that very few people could make a good living out of it, especially during a time when increasing major league salaries were attracting many college-educated men who would have previously chosen other work.

Vance enjoyed hunting and fishing when he retired to Homosassa Springs, Florida, where he had lived since the 1920s. In 1938, Vance became ill with pneumonia. The illness worsened and kept him hospitalized for several months. Vance recovered and became a frequent guest at Brooklyn old-timers games.

He was inducted into the Baseball Hall of Fame in 1955. He learned of his election when a highway patrolman got his attention on a local highway and told him that a photographer was at his house. A Dazzy Vance Day celebration was held in Brooklyn. Biographer John Skipper characterized his Hall of Fame induction as “subdued” compared to the celebration in Brooklyn.

Vance died of a heart attack in 1961 in Homosassa Springs. His obituary in The Sporting News said that he had been under a doctor’s care but that he was active and thought to be in relatively good health when he died. His survivors included his wife Edyth and a daughter.

In 1981, Lawrence Ritter and Donald Honig included him in their book The 100 Greatest Baseball Players of All Time. Vance is mentioned in the 1949 poem “Line-Up for Yesterday” by Ogden Nash: