On February 18, 1946, he was appointed the sixth Bishop of Superior by Pope Pius XII. Meyer received his episcopal consecration on the following April 11 from Archbishop Moses Kiley, with Bishops Aloysius Muench and William O'Connor serving as co-consecrators, in the Cathedral of St. John the Evangelist. He was promoted to the seventh Archbishop of Milwaukee on July 21, 1953 before being named the fifth Archbishop of Chicago on September 19, 1958.
Despite skepticism, Meyer was created Cardinal Priest of S. Cecilia by Pope John XXIII in the consistory of December 14, 1959. He later participated at the first three sessions of the Second Vatican Council, from 1962 to 1964, and sat on its Board of Presidency. During the Council, Meyer showed himself to be of liberal tendencies and was viewed as the chief intellectual among the participating American hierarchy. The scholarly and often shy prelate supported religious liberty, but strongly condemned racism, giving speeches alongside Martin Luther King, Jr. and warning his clergy "not to foster the flame of racial hatred". Meyer was also one of the cardinal electors in the 1963 papal conclave, which selected Pope Paul VI.
He served as Archbishop of Chicago until his death from a heart attack after an operation to remove a malignant brain tumor in Mercy Hospital, at age 62. He is buried in the cemetery of the University of Saint Mary of the Lake in Mundelein, Illinois.