Its shorter southern segment extends 19.529 miles (31.429 km) from SD 50 northwest of Tabor to U.S. Route 18 (US 18) west of Olivet.

Its much-longer northern segment extends 174.995 miles (281.627 km) from SD 262 northwest of Emery, through Howard, De Smet, and Webster, to the North Dakota state line.

North of 293rd Street, it crosses over Dawson Creek and enters the southeastern part of Scotland.

An intersection with Main Street leads to the business district of the city, as well as the Landmann–Jungman Memorial Hospital.

An intersection with CR 2 (Dollard Street), which is signed as a truck route, leads to Lake Henry.

After the highway leaves Scotland, it intersects 291st Street, where it enters the south-central part of Hutchinson County.

Just north of this intersection, the highway crosses over South Branch Lonetree Creek.

Just north of 236th Street, it skirts along the eastern edge of the Burke Slough State Public Shooting Area.

The two highways travel concurrently to the east, while the roadway continues to the north as 427th Avenue.

Just west of Howard, the highways split, with SD 25 taking 433rd Avenue to the north.

At an intersection with CR 6 (224th Street), it crosses over the West Fork Vermillion River.

North of CR 18 (208th Street), it enters the south-central part of De Smet.

In the main part of the city, it intersects US 14 (Laura Ingalls Wilder Historic Highway).

An intersection with 3rd Street leads to Avera De Smet Memorial Hospital.

Immediately, it curves to the north-northwest and passes the De Smet Fire and Rescue.

North of 197th Street, it curves to the north-northwest and passes Cherry Lake to the west.

At an intersection with the western terminus of CR 40 (190th Street), the two highways split, with SD 25 continuing to the north.

Between 184th and 183rd streets the highway travels through the central parts of Hamre State Public Shooting Area.

An intersection with the appropriately-named Hospital Drive and 14th Avenue leads to the Sanford Webster Medical Center.

An intersection with the northern terminus of Main Street leads to the International Vinegar Museum.

East of an intersection with 436th Avenue and the northern terminus of Third Street, it leaves Roslyn.

An intersection with CR 16 (122nd Street) leads to Fort Sisseton State Park and South Buffalo Lakeside Use Area.

An intersection with Northside Drive leads to Roy Lake State Park.

Just north of this intersection, the highway passes the majority of Hoop Lake to the east.

Between Main Street and the northern terminus of Washington Avenue, it passes the city hall.

SD 25 turns left and heads to the north again, while 105th Street continues to the east.

It continues northward until it meets its northern terminus, an intersection with 102nd Street SE at the North Dakota state line.

The SD 25 designation was applied northward from this intersection as construction of the roadway was completed.

Originally, SD 25 went through Howard, but was shifted west approximately 1 mile (1.6 km) in the early 1950s.

In the mid-1950s, the highway was shifted eastward to travel straight north from De Smet to US 212 9 miles (14 km) east of Clark.