His parents apparently were able to send St. Denis to France to further his education. In late 1699, St. Denis sailed from La Rochelle with the second expedition of Pierre Le Moyne, Sieur d'Iberville (a relative by marriage), arriving in Louisiana. St. Denis commanded a fort on the Mississippi River and another at Biloxi Bay. He also explored to the west of the bay and upstream, where he journeyed to the lower Red River. These expeditions brought St. Denis into contact with the Karankawa and Caddo tribes and taught him invaluable wilderness skills specific to the area.
Antoine Laumet de La Mothe, Sieur de Cadillac, sent St. Denis and a company of men from Mobile in September 1713. St. Denis arrived in Natchitoches later that year leaving goods for safekeeping. From there St. Denis traveled to the lands of the Hasinai Confederacy and from there to Spanish outposts on the Rio Grande.
At San Juan Bautista, Coahuila, Commander Diego Ramón placed St. Denis under house arrest while awaiting instructions from Mexico City on what to do with the foreigner charged with violating Spanish trade restrictions. In the meantime, St. Denis courted and won the promise of marriage from Ramón's beautiful step-granddaughter, Manuela Sanchez. St. Denis was ordered to Mexico City and defended himself well enough to be appointed the commissary officer of the Ramón expedition charged with founding Spanish missions in East Texas.
St. Denis returned to San Juan Bautista and married Manuela in early 1716. In the years 1716-1717 he traveled to East Texas to participate in the founding of six missions and a presidio. He returned to San Juan Bautista in April 1717, but with the death of Louis XIV and the conclusion of the War of Spanish Succession, French-Spanish cooperation had ended. St. Denis was then sent to Mexico City for a second time but escaped before being hauled to Spain as prisoner. St. Denis made his way to Natchitoches by February 1719. Spanish officials permitted Manuela to join him and the couple spent their remaining years there at the French outpost on the Red River.
On 10 January 1743, he wrote to Jean-Frédéric Phélypeaux, comte de Maurepas, at Versailles indicating that he could no longer perform his duties as commandant of Natchitoches. He also asked permission to retire to New Spain with his wife and children, which was denied. St. Denis died at Natchitoches on 11 June 1744. He was survived by his wife and five children, one of whom was married briefly to Athanase de Mézières.