While in Pittsburgh awaiting repairs on The Champion, Miffin Kenedy met John Saunders, a United States Army major and engineer who was seeking craft for use on the Rio Grande River during the Mexican War. Hired to assist Saunders, Kenedy commanded The Corvette to New Orleans, Louisiana. His experience in navigation proved invaluable in the transport of soldiers and supplies to the Rio Grande. At the end of the war, Kenedy conducted a pack train to carry merchandise to Monterrey, Mexico. In 1850, Miffin Kenedy and Richard King launched M. Kenedy and Company, their steamship partnership. For the next two decades, M. Kenedy dominated steamboat trade on the Rio Grande. Kenedy soon branched into sheep ranching with the purchase of Merino in Pennsylvania. Despite a fire and losses from drowned animals while in transit, he brought ten thousand sheep in 1854 to Hidalgo County in South Texas. From 1859 to 1860, Kenedy was the captain of a company under Samuel P. Heintzelman in a campaign against the Mexican folk hero and outlaw Juan N. Cortina.

In 1860, Miffin Kenedy and King bought a portion of the Santa Gertrudis Ranch in South Texas. When the two ended this arrangement, it took thirteen months to divide all their far-flung assets, including a variety of ranch animals from the Nueces to the Rio Grande. With the end of the ranch partnership in 1868, Kenedy bought the Laureles Ranch some twenty-two miles from Corpus Christi. At the time, cattle were used rarely for beef but for tallow and hides. More money could be made in river trade, and the Kenedy-King company had twenty-six boats. Though it had been lucrative, the steamship partnership ended in 1874. Kenedy was among the first in Texas to fence ranch lands. In 1869, the Laureles Ranch was expanded to contain 242,000 fenced acres, which required thirty-six miles of actual length. Kenedy sold the Laureles Ranch in 1882 to a Scottish syndicate that became the Texas Land and Cattle Company. Instead he bought 400,000 acres in Cameron County, since Kenedy County. He named this tract the La Parra Ranch because of the grapevines growing there. Having been successful in steamboating, ranching, and trade, Kenedy in 1876 helped Uriah Lott to construct the Corpus Christi, San Diego and Rio Grande Railroad line from Corpus Christi to Laredo in Webb County. In 1885, he supplied the money and credit for Lott to build seven hundred miles of the San Antonio and Aransas Pass Railway.

In 1852, the 33-year-old Miffin Kenedy married the Roman Catholic Petra Vela de Vidal (1825-1885), the young widow of Col. Luis Vidal of Ciudad Mier, Mexico, who had six children[4] from her previous marriage. Kenedy adopted all of Petra’s children. The couple then had six children together. One, James W. “Spike” Kennedy (1855-1884), operated in the Texas Panhandle his own ranch provided with a crew and two thousand head of cattle from his father. In 1878, Spike Kennedy inadvertently shot and killed Dora Hand, a popular dance hall singer and actress in Dodge City, Kansas, where he had come after a cattle drive. He escaped conviction after Mifflin Kenedy paid at least $25,000 to town founder Robert M. Wright to obtain an acquittal based on “lack of evidence”. Mifflin and Petra Kenedy, who died some ten years apart, are interred at Buena Vista Burial Park in Brownsville. Mifflin Kenedy died intestate. Mifflin Kenedy’s only surviving son, John Gregory “Don Gregorio” Kenedy, Sr. (1856-1931), purchased the interest of the other heirs in La Parra Ranch. He lived there with his wife, the former Marie Stella Turcotte (1863-1940), a Louisiana native. The couple reared two children, John Gregory, Jr. (1886-1948), and Sarita (1889-1961). In 1910, Sarita married Arthur Lee East, a neighboring rancher; they had no children. With Sarita’s death, this third generation of Kenedys was hence the last. The Kenedy Ranch Museum of South Texas commemorates Mifflin Kenedy’s role in history. It is located in the county seat of Sarita.