Wayne County was formed in 1779, and the first county seat — a town called Waynesborough — grew up around the courthouse on the east bank of the Neuse River. It thrived through the 1830s. Then the Wilmington and Weldon Railroad came through in the early 1840s, several miles away, and people drifted toward the new line. A hotel built at the intersection of the railroad and New Bern Road became the nucleus of a settlement first called Goldsborough's Junction, after Major Matthew T. Goldsborough, an assistant chief engineer with the railroad. The town incorporated in 1847. Local legend insists that supporters spiked the town well with moonshine on election day to encourage votes for the move. By 1861, the new Goldsborough held about 1,500 people. In 1869 the spelling was officially shortened to Goldsboro.

The railroad gave Goldsborough its livelihood and its strategic importance. The Wilmington and Weldon line ran supplies from the Atlantic port at Wilmington northward to Confederate armies fighting in Virginia. Both sides knew it. In December 1862, Union General John Foster led troops out of New Bern with orders to destroy the bridge at Goldsborough. He succeeded on December 17, burning the bridge and overpowering its small Confederate garrison. The bridge was rebuilt within weeks. In March 1865, General Sherman's army — having burned its way through Georgia and the Carolinas — converged on Goldsborough with the forces of General Schofield. For three weeks, more than 100,000 Union soldiers occupied the city. Some never left, settling in town after Appomattox.

After Reconstruction, Wayne County sat inside what political historians remember as the Black Second — North Carolina's 2nd congressional district, named for its majority-Black population. The Second elected four Republican African Americans to Congress in the 19th century, three of them after Reconstruction had formally ended. George Henry White was the last, an attorney elected in 1896 who served two terms before disenfranchisement laws drove Black voters off the rolls. As the legal architecture of segregation hardened in the 1880s, the state authorized a psychiatric facility in Goldsborough to serve Black North Carolinians — a separate hospital that became Cherry Hospital and operated as the only mental health institution available to Black citizens until the 1960s. The history of Cherry Hospital is told separately, but it cannot be separated from Goldsboro's own.

In April 1942, the US Army Air Forces opened Seymour Johnson Field on the eastern outskirts of Goldsboro. The base was named for a Navy pilot from Goldsboro who had been killed in 1941. It became Seymour Johnson AFB in 1947 when the Air Force became an independent service. The base reshaped the city. Population grew. Businesses followed. Today the 4th Fighter Wing flies F-15E Strike Eagles from Seymour Johnson; the boom of afterburners is part of life in Goldsboro. The 1961 Faro incident — the broken-apart B-52 and its two hydrogen bombs — happened on a flight that originated from this base. A highway historical marker on US 70 remembers what almost happened. The unrecovered uranium remains, fenced off, in the soil twelve miles north.

Goldsboro Milling Company is now among the largest pork producers in the United States. The city is also a major turkey producer. The Borden Manufacturing Company, the First Presbyterian Church, the L. D. Giddens jewelry store, Goldsboro Union Station, and several private homes are listed on the National Register of Historic Places. The Oheb Sholom synagogue's Romanesque Revival building, completed in 1886, is one of fewer than a hundred 19th-century synagogues still standing in the United States — the second oldest synagogue building in North Carolina. Andy Griffith taught English, drama, and music at Goldsboro High School before he was anyone famous. Anne Jeffreys, born here in 1923, made her way to Broadway and Hollywood. Mark O'Meara, who won the 1998 Masters and British Open, came from here. So did Coby White, who played for the Chicago Bulls before being traded to the Charlotte Hornets. The Cliffs of the Neuse rise 90 feet above the river just south of town, in a state park that preserves the kind of geological feature most of the coastal plain lacks.