From St. Louis : Mark Twain Birthplace State Historic Site is approximately 130 miles from the St. Louis Gateway Arch; the trip will take about two and one-half hours depending on traffic. Travel west on I-70 to Exit 210B toward Wentzville/Hannibal. Merge onto U.S. Hwy. 61 N for 48 miles. At Bowling Green, take U.S. Hwy. 54 west for 12 miles. Approximately three miles past Curryville, take Hwy. 154 west for 13 miles. Then take Hwy. 19 north for 11 miles. Turn left back onto Hwy. 154 and travel west through Perry for eight miles. Turn north onto Hwy. 107 and continue for three miles. Turn east onto Route U, then turn onto the first paved road to the right, Shrine Road, and follow it to the historic site.

From Jefferson City : Allow one and half hours for the trip. Take U.S. Hwy. 54 East to Mexico. Take Hwy. 22 west for approximately one mile before turning north/right onto Hwy. 15. Continue on Hwy. 15 for 26 miles. Take Hwy. 154 east for 11 miles then turn left/north onto Hwy. 107 and travel three miles. Turn east onto Route U, then turn on the first paved road to the right, Shrine Road, and follow it to the historic site.

From Springfield : Mark Twain Birthplace State Historic Site is approximately 243 miles from Springfield; allow four hours for the trip. Travel north on U.S. Hwy. 65 from Springfield for 50 miles. Near Preston, turn right/east onto U.S. Hwy. 54 and continue through Jefferson City to Mexico. Take Hwy. 22 west for approximately one mile before turning north onto Hwy. 15 and traveling 26 miles. Turn right/east onto Hwy. 154 and continue for 11 miles. Take Hwy. 107 north for three miles then turn east onto Route U. Take the first paved road to the right, Shrine Road, and follow it to the historic site.

From Kansas City : Mark Twain Birthplace State Historic Site is approximately three and one-half hours from downtown Kansas City. Travel east on I-70 for 126 miles. At Columbia, turn left/north onto U.S. Hwy. 63 and continue for 32 miles to Moberly. Turn right/east onto U.S. Hwy. 24. Approximately ten miles east of Paris, turn right/south onto Hwy. 107 and continue for six miles. Turn east onto Route U, then turn onto the first paved road to the right, Shrine Road, and follow it to the historic site.