SR 225 begins in the northeastern part of Calhoun, spurring off of U.S. Route 41 (US 41) at an intersection in central Gordon County.

It meets its northern terminus when it encounters the Tennessee state line approximately 2.2 miles (3.5 km) north of Gregory.

[4] SR 225 is designated as a "Trail of Tears" Highway because of significant cultural remains of the Cherokee Nation along the route.

Included is New Echota, the former capital of the Cherokee Nation (and home to the first Native American language newspaper in the United States) and the Chief Vann House Historic Site, site of the former wealthy Cherokee leader, landowner, and businessman Joseph Vann.

The capital of New Echota is designated as the official beginning of the "Trail of Tears", the forceful removal of thousands of Native American in the 19th century.

[citation needed] The stretch of SR 225 through southern Murray County between the Gordon County line and four-way stop at Spring Place is an extremely dangerous length of highway, with a plethora of serious motor vehicle accidents, including many fatalities, each year.

Reasons for this include excessive speeds by drivers due to the lack of development and multitudes of bad intersections with county roads and private drive-ways.