The Appalachian Mountains and the Mississippi River are two of North America's defining features—but they don't cross paths. They run in fundamentally different orientations.
Source: Lake Itasca, Minnesota (47°N). Mouth: Gulf of Mexico, Louisiana (29°N). Flow: ~3,770 km southward. Drainage: 3.2M km² (41% of contiguous US). It defines the continent's central lowland.
Extent: Newfoundland (Canada) to central Alabama. Length: ~3,200 km. Orientation: NE-SW, parallel to Atlantic coast. Highest: Mount Mitchell, NC (2,037m). They define the eastern highland.
The Mississippi's easternmost headwaters (Minnesota) are ~1,000 km west of the Appalachians' northern terminus. The river's upper basin lies in the glaciated Interior Plains. The Appalachians' western front (Allegheny Plateau) drains to the Ohio River—a Mississippi tributary—but the mainstem Mississippi never enters the mountain chain.
The Ohio River (formed at Pittsburgh by Allegheny + Monongahela, both Appalachian rivers) carries Appalachian water, sediment, and history to the Mississippi at Cairo, IL. This confluence is where the two systems truly meet.
Appalachians: Paleozoic orogeny (480-300 Ma), now eroded roots. Mississippi: Cenozoic river system exploiting the mid-continent rift and glacial history. Different ages, different processes.
They're the continent's two great structural grains—orthogonal, complementary, connected only by tributaries.