The Southeast Ohio region borders West Virginia and is very hilly, lying in the foothills of the Appalachian Mountains. Most of the Wayne National Forest is located in this region, and is ideal for hiking and camping with over 300 miles of trails. Much of it is reclaimed coal mining lands that have been preserved by the federal government. There are also areas for off-roading, fishing, bird watching and equestrian riding. There are approximately 15 state parks in this region which offer recreational activities, with several resorts, cottages and campgrounds for visitors to enjoy. The region borders the Ohio River to the south, an area which has some of Ohio's most scenic and historic sites. Though is one of the largest areas of the state in land area, it is the least populated, and is generally considered fairly rugged. Cities in this region are Athens, well-known for Ohio University, Zanesville and Marietta, the oldest city in Ohio. Historically Marietta was an important Ohio River port, and it offers scenic views of the Ohio River.

Muskingum County is in the northwest portion of the southeastern region of Ohio, and is nearly bisected by the Muskingum River. The county name comes from a Delaware Native American word meaning "town by the river." It is the fourth largest county by land area in Ohio. Zanesville is the county seat and the only city in the county. One attraction in Muskingum County is The Wilds, a 9,000-acre wildlife preserve that is open to the public. The county is also home to Muskingum University, a small university with approximately 4,000 undergraduate and graduate students.

Scioto County is in the southern part of the Southeast region of Ohio, and is bordered by the Ohio River and Kentucky to the south. Portsmouth is the county seat and the only city in the county, but there are many small townships and villages. The name comes from a Native American word related to "deer or "deer-hunting." Attractions include Shawnee State Forest and Park, the largest in Ohio. Other natural areas include Brush Creek State Park, Earl Thomas Conley Park, and a portion of the Wayne National Forest. There are 14 parks within the city limits of Portsmouth. Shawnee State University is located in this county; established in 1986, it is one of Ohio's youngest state universities.

Tuscarawas County is located in the northern part of the Southeast region of Ohio. The name comes from a Delaware Native American word meaning "old town" or "open mouth." New Philadelphia is the county seat and the largest city in the county, with Dover also being a larger city. The county has several museums and historic sites, including historic Schoenbrunn Village, historic Zoar Village, Gnadenhutten Museum and Historical Park, Ohio's oldest existing settlement, and Warther Carvings and Gardens, which displays the carved works of Ernest Warther. There are also many Amish in the area, and visitors can enjoy delicious home-cooked food at restaurants in the area, as well as shops and markets featuring hand-made goods. Atwood Lake Park is a popular destination for boating, canoeing, hiking and there are also several other parks for outdoor recreation. The Ohio and Erie Canalway Towpath Trail also extends into this area from the north.