Gunther grew up in Chicago and attended the University of Chicago, where he was literary editor of the student paper.

From 1924 to 1936, Gunther was assigned to the London bureau of the Chicago Daily News. Gunther writes, "I was at one time or another in charge of Daily News offices in London, Berlin, Vienna, Moscow, Rome, and Paris, and I also visited Poland, Spain, the Balkans, and Scandinavia. I have worked in every European country except Portugal. I saw at first hand the whole extraordinary panorama of Europe from 1924 to 1936."

The books that made Gunther famous in his time were the "Inside" series of continental surveys. For each book, Gunther traveled extensively through the area the book covered, interviewed political, social, and business leaders, talked with average people, reviewed area statistics, and then wrote a lengthy overview of what he had learned and how he interpreted it.

About Inside Europe (published in 1936), Gunther wrote, "This book has had a striking success all over the world. I was fortunate in that it appeared at just the right time, when the three totalitarian dictators took the stage and people began to be vitally interested in them."

In addition to the "Inside" series, Gunther wrote eight novels and three biographies, most notably Bright Nemesis, The Troubled Midnight, Roosevelt in Retrospect (published in 1950) and Eisenhower, a biography of the famous general released in 1952, the year Dwight D. Eisenhower was elected President. In addition, he published several books for young readers, including a biography of Alexander the Great in 1953, and Meet Soviet Russia, a two-volume adaptation of Inside Russia Today in 1962.

The book for which Gunther is best remembered today, however, does not deal with the intrigues of politics: Death Be Not Proud is the story of his son, Johnny, who died of a brain tumor at the age of 17. In the book, the elder Gunther details the struggles that he and his ex-wife went through in attempting to save their son's life: the many treatments pursued (everything from radical surgery to strictly controlled diet), the ups and downs of apparent remission and eventual relapse, and the strain it placed on all three of them. Gunther portrays his son as a remarkable young man – he corresponded intelligently with Albert Einstein about physics – and the heartbreak of his death is told so movingly by Gunther that the book became a best-seller, and in 1975 was made into an Emmy-nominated television movie starring Arthur Hill as John Gunther, Jane Alexander as his wife, and Robby Benson as Johnny. It is a staple of many high-school curricula to this day.

Inside U.S.A. was made into a Broadway revue in 1948, with songs by Howard Dietz and Arthur Schwartz. The production starred, among others, Beatrice Lillie and Jack Haley. It played for 399 performances.

From September 7, 1959 until September 17, 1960, Gunther was host and narrator of a television program on the ABC network entitled "John Gunther's High Road". It originally aired Monday nights at 8:30, but soon switched to Saturday night at 8 p.m., immediately following the Dick Clark variety show. The High Road program consisted of travelogues of various nations around the world. Some of the films were produced especially for this program and others were obtained from other sources. The common thread of all episodes was Gunther's narration, although he had little or nothing to do with the actual content.