Macon lies near the state's geographic center, about 85 miles (137 km) southeast of Atlanta, hence the city's nickname: "The Heart of Georgia".

Macon, which bills itself as the "Cherry Blossom Capital of the World," holds the International Cherry Blossom Festival in late March every year, when 300,000-350,000 Yoshino Cherry Trees bloom around the city. The trees were originally brought to Macon by William Fickling, a local realtor who became known as Macon's Johnny Appleseed after growing the trees in his own yard and giving them away to others in the community.

After the organization of Bibb County in 1822, the city was chartered as the county seat in 1823 and officially named Macon in honor of Nathaniel Macon, who served as the fifth Speaker of the House from 1801 to 1807. As a member of Congress, Macon opposed ratification of the United States Constitution and the Federalist economic policies of Alexander Hamilton. Thomas Jefferson dubbed him "Ultimas Romanorum"--"the last of the Romans."

The kazoo was invented in the 1840s by Macon natives Alabama Vest and Thaddeus Von Clegg. It was first presented to the world at the Georgia State Fair in 1852 as the "Down South Submarine".

The areas along the rivers in the Southeast United States had been inhabited by indigenous peoples for 13,000 years before Europeans arrived, and Macon was founded on the site of the Ocmulgee Old Fields, where the Creek Indians lived in the 18th century. The Creek conducted considerable trade with white settlers and even adopted some European-American customs, but they were forcibly removed to Indian Territory (now Oklahoma) by the federal government in the 1830s during the Trail of Tears.

Macon developed at the site of Fort Benjamin Hawkins, built in 1809 at the fall line of the Ocmulgee River to protect the community and to establish a trading post with Native Americans. The river was formerly known by its Hitchiti name of Ocheese Creek, from which the Creek people derived their name.

Prior to the establishment of Fort Hawkins, the earliest European contact was in 1540 when Hernando DeSoto came through the area. North America's first Christian baptism was recorded when priests in DeSoto's band baptized two Native American boys in the Ocmulgee River near what is now Carolyn Crayton Park.

In June 2021, city officials announced plans to build the "world's largest advanced plastics recycling plant," promising that the 5 million-square-feet facility would divert 400,000 tons of plastic waste from landfills and incinerators.

Although the city was bypassed by Union General William Tecumseh Sherman during his famous March to the Sea, it was was taken by Union forces during Wilson's Raid on April 20, 1865--just six days before General Joseph E. Johnston's surrender of all Confederate troops in the Carolinas, Georgia, and Florida to Sherman in North Carolina.

In 1836, the Georgia Conference of the Methodist Episcopal Church founded Wesleyan College in Macon. Wesleyan was the first college in the United States chartered to grant degrees to women.