[7][8] Long before modern-day migration patterns, the Mexican Federal Highway 15 corridor was also the corridor many Spanish expeditions followed in their colonization and founding of settlements that would later become communities in the modern-day Mexican northwest (such as Tepic, Mazatlán, and Hermosillo) and U.S. southwest (such as Tucson and Yuma in Arizona, and Los Angeles, San Francisco, and other cities in present-day California).

The two highways merge until Santa Ana where Fed-2 (whose western corridor through Sonora serves as a critical link between the Baja California Peninsula and mainland Mexico) separates, heading westward towards its terminus in Tijuana.

Views of the Sea of Cortez accompany motorists for this stretch of roadway until Fed-15 turns inland towards Ciudad Obregón crossing the Rio Yaqui.

South of Mazatlán at Villa Union, Fed-15 intersects with Fed-40, an important east–west highway offering motorists a connection between the Pacific coast and the interior of Mexico (terminating at the border city of Reynosa, Tamaulipas) across the Sierra Madre Occidental.

In northwestern Nayarit, Fed-15 links the communities of Acaponeta, Santiago Ixcuintla (via Fed-72), and the colonial era port city of San Blas (via Fed-74) to the state capital of Tepic.

Departing from the Mexican west coast, the highway crosses the Rio Santiago, ascends steep mountains covered in lush forest before descending into Tepic and continuing eastward across the state.

In Tepic, Fed-15 travels along Avenida Insurgentes as a major urban artery, with some portions of the roadway including tunnels, separating the highway from some of the city's surface streets.

West of Guadalajara near the suburb of La Venta del Astillero, Fed-15 intersects with Fed-70 which provides highway access to Puerto Vallarta.

After entering Guadalajara, Fed-15 suddenly turns southward along the city's southwestern edge and travels through small communities along the southern shore of Lake Chapala (intersecting Fed-13) before crossing into the state of Michoacán.

Within the lush hills of Michoacán, Fed-15 continues its journey along the shore of Lake Chapala, turning south through Sahuayo where it joins Fed-110, traveling together towards the city of Jiquilpan.

In eastern Michoacan Fed-15 reverts to a two-lane rural highway crossing agricultural communities and pine forests as the roadway ascends into mountain ranges.