Before 1500 a. d., the area of land that is today known as the united states was inhabited by native americans. they often settled in geographic regions for the same reasons as european and asian immigrants. what is the reason people most likely settled along the mississippi river? the mississippi river valley provided high ground for protection. the mississippi river valley was never settled by native americans. the mississippi provided food and transportation for its inhabitants. the mississippi river valley was difficult to farm because of floods.