US 290 begins from I-10 roughly southeast of the small town of Segovia. It begins to travel due east through rural farmlands in the Texas Hill Country before reaching Harper, where it is the main west–east road in the town. Afterwards, US 290 begins making slight curves as it crosses through several creeks and tributaries amidst additional farmland, where it eventually joins US 87 and runs as Main Street through Fredericksburg. The two highways travel together for eleven blocks in downtown Fredericksburg before US 87 splits south of US 290 at an intersection directly south of the National Museum of the Pacific War. Traveling due south, US 290 returns to an eastward path after crossing the Pedernales River, where it serves as a major artery for Fredericksburg's agricultural district, including Wildseed Farms. The highway then runs parallel to the Pedernales River, and after passing Stonewall, serves the south side of LBJ Ranch. As the Pedernales River arcs further north, US 290 continues east through several wineries before approaching Johnson City and bordering the north side of the LBJ Johnson City Unit. US 290 runs along Main Street throughout downtown Johnson City as it joins US 281 and heads south.