In 1900 the family moved to Baltimore, Maryland. In 1906 Christopher entered Haverford College, graduating in 1910 as [valedictorian]. He then went to New College, Oxford, for three years on a Rhodes scholarship, studying modern history.

In Oxford a volume of his poems, The Eighth Sin (1912), was published. After graduating from Oxford, Morley began his literary career at Doubleday, working as publicist and publisher's reader. In 1917 he got his start as an Editor for Ladies' Home Journal (1917–1918), then as a newspaper reporter and newspaper columnist in Philadelphia for the Philadelphia Evening Public Ledger.

In 1913 Morley completed his Oxford studies and moved to New York City, New York. On 14 June 1914, he married Helen Booth Fairchild, with whom he would have four children, including Louise Morley Cochrane. They first lived in Hempstead, and then in Queens Village. They then moved to Philadelphia, Pennsylvania, and in 1920 they made their final move, to a house they called "Green Escape" in Roslyn Estates, New York. They remained there for the rest of his life. In 1936 he built a cabin at the rear of the property (The Knothole), which he maintained as his writing study from then on.

Morley's first novel, Parnassus on Wheels, appeared in 1917. The protagonist, traveling bookseller Roger Mifflin, appeared again in his second novel, The Haunted Bookshop in 1919.

In 1920 Morley returned to New York City to write a column (The Bowling Green) for the New York Evening Post.

From 1928 to 1930, Morley co-produced theater productions (dramas) at his theaters in Hoboken, New Jersey, which he had "deemed the last seacoast in Bohemia".

He was one of the founders and a longtime contributing Editor of the Saturday Review of Literature. A highly gregarious man, he was the mainstay of what he dubbed the "Three Hours for Lunch Club". Out of enthusiasm for the Sherlock Holmes stories, he helped found The Baker Street Irregulars and wrote the introduction to the standard omnibus edition of The Complete Sherlock Holmes. He also wrote an introduction to the standard omnibus edition of The Complete Works of Shakespeare in 1936, although Morley called it an "Introduction to Yourself as a Reader of Shakespeare". That year, he was appointed to revise and enlarge Bartlett's Familiar Quotations (11th edition in 1937 and 12th edition in 1948). He was one of the first judges for the Book of the Month Club, serving in that position until the early 1950s.

Author of more than 100 novels, books of essays, and volumes of poetry, Morley is probably best known for his 1939 novel Kitty Foyle, which was made into an Academy Award-winning movie. Another well-known work is Thunder on the Left (1925).

In 1951 Morley suffered a series of strokes, which greatly reduced his voluminous literary output. He died on 28 March 1957, and was buried in the Roslyn Cemetery in Nassau County, New York. After his death, two New York newspapers published his last message to his friends:

For most of his life, he lived in Roslyn Estates, Nassau County, Long Island, commuting to the city on the Long Island Rail Road, about which he wrote affectionately. In 1961, the 98-acre (40-hectare) Christopher Morley Park on Searingtown Road in Nassau County was named in his honor. This park preserves as a publicly available point of interest his studio, the "Knothole" (which was moved to the site after his death), along with his furniture and bookcases.