The neighborhood contains numerous notable examples of mid-20th century residential architecture, with houses designed by architects such as Charles I. Barber, Benjamin McMurry, and Francis Keally.

[2] Originally an agricultural area called Looney's Bend, the modern Sequoyah Hills neighborhood is largely rooted in the development efforts of 1920s-era visionary entrepreneurs E. V. Ferrell, who developed the Scenic Drive area, and Robert L. Foust, who established the "Talahi" subdivision in the vicinity of Cherokee Boulevard and Talahi Drive.

[2] Foust and Ferrell advertised their respective developments as utopian getaways where Knoxville's elite could escape the ills of congested city life.

What is now Sequoyah Hills was inhabited by Native Americans as early as the Late Woodland period (c. 500–1100 A.D.), as indicated by a 1,000-year-old Indian mound that rises in the median of Cherokee Boulevard.

[6] In 1796, Moses Looney, who had served in various capacities with the failed State of Franklin during the 1780s,[7] acquired a 700-acre (280 ha) tract of land in what is now Sequoyah Hills.

Other early landowners in the Sequoyah Hills area included future Knoxville mayor James Park, who purchased a 200-acre (81 ha) tract in 1804; William Lyon, who built a house and mill near the modern intersection of Lyon's View Pike and Northshore Drive around 1810; and Drury Armstrong (builder of Crescent Bend), who acquired a large tract of land west of modern Scenic Drive in 1846.

[2] In 1890 Francis Huger, superintendent of the East Tennessee, Virginia and Georgia Railway, acquired over 450 acres (180 ha) in Sequoyah Hills with the intent of moving a steel mill to the area.

[2] Knox County road commissioner Peter Blow built a house on the south bank of the river opposite Sequoyah Hills in 1910, where he operated a ferry.

[8] With the advent of the automobile, affluent Knoxvillians began fleeing the congested urban neighborhoods for more spacious areas on the city's periphery.

[2] In 1921, Regal Manufacturing president S. D. Coykendall commissioned noted Knoxville architectural firm Barber & McMurry to build a house on what is now Scenic Drive.

[3] In 1926 Robert Foust, a partner in the real estate firm Alex McMillan Company, purchased a 100-acre (40 ha) tract of land on the southeast section of Looney's Bend with plans to develop a premier subdivision for Knoxville.

[3] Before the stock market crash ruined his development efforts in 1929, Foust managed to complete several landscape improvements in the proposed Talahi subdivision.

[3] Notable residents of Sequoyah Hills have included Senator Howard H. Baker, Jr., businessman Jim Clayton (owner of Clayton Homes), author Alex Haley, members of the Haslam family including Governor Bill Haslam,[2] author Cormac McCarthy, actress Patricia Neal, Tennessee Volunteers football coach Robert R. Neyland, actor David Keith, Knoxville mayors George Roby Dempster and Benjamin Morton, and photographer James Edward Thompson.