Proceeding northbound, US 181 runs through the following Texas counties: Nueces, San Patricio, Bee, Karnes, Wilson, and Bexar.

US 181 shares a duplex with SH 188 and US 77 Business in Sinton, and makes a right turn at San Patricio Street, proceeding northbound.

US 181 business runs through downtown Beeville while drivers passing by can use the US 181 freeway bypass on the east side of town.

North of Beeville US 181 passes through a number of unincorporated towns including Normanna, Pettus, and Tuleta before reaching Kenedy.

North of Floresville US 181 passes through the town limits of Elmendorf before intersection with State Loop 1604 (Anderson Loop, surrounding San Antonio), and ends 8 miles north at its northern terminus at I-37, just south of I-37 and I-410 on San Antonio's far south side.

[1] The completion of I-37 in San Antonio during the 1970s resulted in the truncation of US 181 to its interchange with that freeway, although the AASHTO route log in 1989 stated that US 181 extended northward along I-37 to a common northern terminus at I-35/US 281.

[2] In 2003, TXDOT began planning to replace the existing Corpus Christi Harbor Bridge due to maintenance and safety issues as well as to provide long term access to the Port of Corpus Christi to larger ship vessels (including Panamax).

which is west of the old bridge, would begin at the northern terminus of SH 286 (exit 1C on I-37) and cross the Corpus Christi Ship Channel before merging with the current US 181 alignment.

Although not officially concurrent with SH 72, the signage in the area directs traffic from one segment to the other, effectively completing the loop.