A painting by Charles Sullivan shows locally built boats off the shore of Marietta, Ohio, ca. 1840. Photo: Ohio History Connection

In the five decades since publishing his first book, “The Johnstown Flood,” David McCullough has become perhaps our best-loved chronicler of America’s past. He is also one of our most decorated, having earned two Pulitzer Prizes (for “John Adams” and “Truman”) and two National Book Awards (for “The Path Between the Seas” and “Mornings on Horseback”), not to mention the Presidential Medal of Freedom. Over his long career, Mr. McCullough has taken on a few epic stories, such as the building of the Panama Canal. But more often he has chosen to shine a lantern into the underappreciated corners of American history, such as the 1889 flood in Johnstown, Pa., or, for that matter, the life of Harry Truman. His latest book, “The Pioneers,” continues in this vein, chronicling the first permanent white settlement in the Northwest Territory. In the process, it sheds light on pioneers everywhere.

The Northwest Territory nearly didn’t pass to the United States at all At the end of the Revolutionary War, Britain was determined to retain all land northwest of the Ohio River. But during negotiations for the Treaty of Paris, John Adams insisted: “No! Rather than relinquish our claim to the western territory, I will go home and urge my countrymen to take up arms again.” And so a vast tract west of the Allegheny Mountains and east of the Mississippi—more than a quarter-million square miles, comprising present-day Ohio, Indiana, Illinois, Michigan, Wisconsin and much of Minnesota—became part of the United States, doubling the nascent nation’s land area.

It took the Founding Fathers a few years to decide what to do with the windfall. Then in July 1787, the New York-based Congress of the Confederation, the precursor of the U.S. Congress, passed the Northwest Ordinance, establishing how the new territory would enter the Union. Crucially, the ordinance outlawed slavery in the region; it also promised that the “utmost good faith shall always be observed towards the Indians.”

Speculators had begun to circle even before the ordinance was signed. In March 1786, a group of Revolutionary War veterans had convened at a Boston tavern and founded the Ohio Company of Associates, intent on buying a great swath of the territory. Manasseh Cutler, a 43-year-old polymath with doctorates in divinity, medicine and law, was chosen to travel to New York and persuade a skeptical Congress to accept the company’s terms: $1 million dollars for 1.5 million acres. When the sale was approved, in July 1787, Cutler was awarded nearly 5,000 acres for his services.

The first 48 pioneers left Massachusetts and Connecticut that December. Over the next four months, the men slogged 700 miles through the Alleghenies, then built boats and drifted down the Ohio. On April 7, 1788, they reached the spot that Manasseh Cutler had selected, a handsome, fertile tract at the confluence of the Ohio and Muskingum rivers. On hand to welcome them was a committee of some 70 Native Americans, led by the Delaware chief Captain Pipe, who declared that the white men would be their brothers “as long as the sun and moon endured.” Just in case, though, the pioneers set to building a massive stockade. They also cleared the forest and constructed a New England-style village, which they called Marietta, in honor of Marie Antoinette of France, for her supposed role in persuading Louis XVI to aid the Americans during the Revolution.

The settlers’ first years were predictably hard, bringing starvation, measles, smallpox and rising tensions with the Native Americans. Mr. McCullough is above all a storyteller, and he relates the pioneers’ travails in his understated, avuncular way, letting the narrative unfold at a relaxed pace and taking time for the arresting detail, the informative digression, the revealing quotation. He shows his characters in action and wherever possible lets them speak in their own words. Due scope is given to Marietta’s early leaders, who besides Cutler included Rufus Putnam, Revolutionary War hero and chairman of the Ohio Company, and Arthur St. Clair, ex-general and first governor of the Northwest Territory. But also included are key settlers such as Joseph Barker, a shipwright and architect, and Samuel Hildreth, a medical doctor and local historian. And Mr. McCullough doesn’t overlook the ranks of farmers, blacksmiths, carpenters, cobblers and gunsmiths who went to Ohio in search of a better life. As he writes, “West was opportunity. West was the future.”

When word of the bountiful bottomland reached back east, thousands more would-be settlers caught “Ohio Fever.” As more trees were felled and more houses built, the Native Americans grew less welcoming. In January 1791, a raiding party of Delawares and Wyandots massacred 14 pioneers not far from Marietta. Retaliation followed retaliation, until on Nov. 4, on the banks of the Wabash River, a thousand warriors surprised a poorly trained army led by Gov. St. Clair, killing more than 800 soldiers, women and children. One of the chiefs on the field that day was Captain Pipe, who just a few years before had welcomed the newcomers as brothers.

The stunning defeat prompted the very first congressional investigation, which exonerated Gov. St. Clair of any blame for the debacle. Then in August 1794, about 2,000 troopers under “Mad Anthony” Wayne routed the Indians at the Battle of Fallen Timbers; the following year their chiefs signed the Treaty of Greenville, ending the Northwest Indian War and clearing the way for more white settlement.

Although Mr. McCullough sketches in treaties and other bits of historical context, his focus never strays far from life in Marietta. In the coming years, a post office was built in the town, along with a library, a courthouse and a college. Brick and stone houses took the place of log cabins. As traffic increased on the Ohio River, shipbuilding became a major industry. In 1803, Ohio entered the Union as the 17th state and the first carved from the Northwest Territory.

But the hard times weren’t over. In the new century, Marietta was buffeted by the War of 1812, outbreaks of yellow fever, typhoid and influenza, a flood, and even earthquakes. By 1850, when it was a stop on the Underground Railroad, the town was still home to fewer than 4,000 souls. By 1863, when Mr. McCullough ends his story, with the death of Dr. Hildreth, the population of Ohio had swelled to two million, and Marietta had long been eclipsed by Cleveland and Cincinnati.

Though “The Pioneers” is ostensibly the story of one settlement, Mr. McCullough clearly intends it as more than that. In his acknowledgments, he writes that the book is “such as I had long hoped I might one day attempt, ever since I first saw Thornton Wilder’s play Our Town.” With its tight focus and ensemble cast, “The Pioneers” does read as a kind of “Our Town on the Ohio.” And just as Wilder’s work is the story not of one New England town but of all such communities, so “The Pioneers” is the account not just of one Ohio settlement but of myriad such places across America, where innumerable immigrants (as the settlers were known) came to make a fresh start in a strange land. It is a story as resonant today as ever.

—Mr. Helferich’s most recent book is “An Unlikely Trust: Theodore Roosevelt, J.P. Morgan, and the Improbable Partnership That Remade American Business.”