San Patricio was founded in 1829 by the empresarios James McGloin and John McMullen after they received permission from the Mexican government on August 16, 1828, to settle 200 Irish Catholic families in Texas. After recruiting settlers in New York, the empresarios hired the New Packet and Albion to transport the colonists to their new home. The first settlers arrived at El Cópano and Mesquite Landing in late October 1829 and made their way to the old mission at Refugio, where they remained for some time. They eventually chose a townsite where the Camino Real from Goliad to Laredo and the Atascosito Road from Louisiana crossed the Nueces River. It is not known just exactly when the settlers moved from Refugio to the Nueces River site; however, by November 18, 1830, the move was completed. The ancient fort of Lipantitlán was across the river less than two miles distant. The colonists put up temporary shelters of poles chinked with mud and grass. Since there was very little timber for log cabins, they built picket houses by digging trenches and standing small tree trunks upright in them. Roofs were made of thatch, and mud filled the cracks in the walls. Land commissioner José Antonio Saucedo arrived in October 1831 to issue land grants to eight settlers. A townsite four leagues square, called Villa de San Patricio de Hibernia in honor of Ireland's patron saint, had been laid out by surveyor William O'Docharty. In 1834 José María Balmaceda, the new land commissioner, returned to issue another seventy-six land grants. Local autonomy under Mexican rule was increased in 1834 when the municipality of San Patricio was established. William O'Docharty was named alcalde, and Thomas Adams, Francisco De León, Francisco Leal, and Patrick O'Boyle were elected aldermen. It appears that the residents of San Patricio were not caught up immediately in the revolutionary spirit that prevailed over most of Mexican Texas in 1835; however, representatives from San Patricio participated in all conventions except the first (see TEXAS REVOLUTION). With the help of men from San Patricio, Capt. Ira Westover and his men from Goliad captured Fort Lipantitlán in December 1835. In early 1836 the Matamoros expedition began to move to the front, with the intention of marching on Mexico; on February 27 Gen. José Urrea surprised Col. Francis W. Johnson's men in San Patricio and killed or captured most of the unit. The Texans were buried in the Old Cemetery on the Hill at San Patricio. After the battle of San Patricio the Mexican army became an ever-present menace. San Patricio became a ghost town as the colonists fled to Victoria and other refuges, leaving their homes and livestock unprotected. Later the municipality was declared a depopulated area, and so it remained until Gen. Zachary Taylor arrived in South Texas in 1845. He stationed a dragoon of troops in San Patricio and returned a semblance of law and order to the frontier town.
When the Texas Legislature demarked San Patricio County on March 17, 1836, San Patricio was designated the county seat. A post office was established in 1848 with C. H. John Rofs as postmaster. San Patricio was incorporated by an act of the legislature on February 7, 1853. For the next two decades the city grew, as more and more settlers arrived and farming and ranching became more profitable. The overland Cotton Road crossed the Nueces River at San Patricio, and the wagon crews stopped to buy supplies and drink in the local saloon. Outlaws preyed on the wagon trains, giving rise to tales about crews who buried their gold south of the river. In the 1880s San Patricio had several churches, schools, cotton gins, a gristmill, and a population of 200. St. Joseph's Convent, a school for girls, and St. Paul's Academy for boys were established in 1876. By 1890 the population was 400. After Sinton became the county seat in June 1894, San Patricio began to decline. In 1901 a citizens' group persuaded the state legislature to disincorporate the city. For over seventy years San Patricio was all but forgotten, until in 1972 the city of Corpus Christi sought to annex an area on the Nueces River that would have given it jurisdiction over the old town. The citizens of San Patricio rose to the challenge and defeated the annexation attempt; they reincorporated on August 12, 1972. An awareness of the heritage of San Patricio has caused a rebirth of interest in its history. Annual world championship rattlesnake races on St. Patrick's Day have been used by the San Patricio Restoration Society as a means to raise funds to preserve the city's landmarks. Enough money was raised to rebuild the courthouse of 1872 according to original specifications; it was dedicated in 1987. In 1990 the population was 369. The population dropped to 318 in 2000.