Born in Trois-Rivières, Quebec, Pierre was the youngest son of René Gaultier de Varennes and Marie, the daughter of Pierre Boucher, the first Governor of Trois-Rivières. Part of the Ancien Régime, the Gaultier family of aristocrats came from the Anjou area of France. Pierre was educated at a Jesuit seminary in Quebec. At the age of 14 he received a cadet’s commission in the colonial regulars. In 1704 and 1705 he took part in the armed struggle known as Queen Anne's War in the present day United States.

At 22 years of age, he enlisted in the French Army, fought in Flanders during the War of the Spanish Succession and was seriously wounded. After recovering from his injuries and being paroled as a prisoner of war, Gaultier returned to Canada and married in 1712. He farmed and traded furs to support his family. In 1727 he was appointed to command at the fort at Nipigon.

In 1728 La Vérendrye was appointed commandant of the French posts, including Fort Kaministiquia, (present day Thunder Bay, Ontario, in Canada), on the north shore of Lake Superior. As commandant, La Vérendrye came to know a Cree guide, Auchagah. Auchagah made a map of canoe routes between Lake Superior and Lake Winnipeg based on his and other Cree experience. La Vérendrye became convinced that there was a gulf like western sea '(mer du couchant) that opened on the Pacific from the middle latitudes of North America.

In 1731 La Vérendrye began his explorations in earnest, with the objective to find a route to the Western Sea. Between 1731 and 1737, he built several trading posts between Lake Superior and Lake Winnipeg, assisted by his four sons and a nephew. These included Fort St. Pierre at the west end of Rainy Lake in 1731; Fort St. Charles near Angle Inlet on Lake of the Woods in 1732; Fort La Foret on the Winnipeg River in 1733; and Fort Maurepas on the Winnipeg River near present day Selkirk, Manitoba in 1734. Until at least 1760, these forts were important bases of operations because of the fur trade and their locations between Montreal and points farther west. These were the first European settlements west of Lake Superior since Jacques de Noyon wintered over at Rainy Lake in 1688.

In 1738 La Vérendrye travelled with Assiniboine guides southwest to the area of the Missouri River in what is now North Dakota, United States. There he was introduced to the Mantannes (Mandans), a Siouan speaking agricultural people living in permanent villages along the Missouri. During that trip, he established two forts, Fort Rouge and Fort La Reine, in what is now Manitoba in Canada. Two of his sons explored the area southwest of the Mantannes, reaching the Big Horn Mountains, the Black Hills and returning via the Missouri and what is now Pierre, South Dakota. It may have been on this trip that he found the alleged Vérendrye Runestone.

The forts built to the north and west by people under La Vérendrye's command created a large area in the west for French traders. In addition to Fort Rouge and Fort La Reine, on the site of present day Portage-la-Prairie, established in 1738, New France built other posts linked to the fur trade: Fort Dauphin (Winnipegosis, Manitoba); Fort Bourbon, to the northwest of Lake Winnipeg; and Fort Paskoya, to the northwest of Cedar Lake.

La Vérendrye resigned as commander of the Western Posts in 1744 after being unable to convince his superiors that exploration of rivers such as the Saskatchewan would lead them to rivers flowing west into the Western Sea. In 1746 he again became the western commander and returned to the east in 1747. While planning further exploration of the Saskatchewan River and points west, he died at Montreal on December 5, 1749. La Vérendrye was posthumously awarded the Order of Saint Louis by King Louis XV of France.

Numerous places were named in his honor: La Vérendrye Provincial Park in Ontario, and La Vérendrye Wildlife Reserve and Boulevard de La Vérendrye Montreal in Quebec; The neighbourhood of Varennes in the St. Vital district of Winnipeg, and rue La Vérendrye and Parc La Vérendrye in the Saint Boniface district in Winnipeg; Verendrye Electric Cooperative in North Dakota.