La Salle County was created from Bexar County in 1858 and organized in 1880. It is named for Rene Robert Cavalier, Sieur de La Salle, a French explorer who followed the Mississippi River from its headwaters to the Gulf of Mexico from 1678-1682. La Salle organized another expedition to explore the Mississippi in 1684. He missed the Mississippi and landed in the Matagorda Bay are in February, 1865. La Salle established Fort St. Louis and made several expeditions into Texas during the next two years before he was murdered by his own men.
 
Although La Salle failed to establish a permanent French presence in Texas, he did give French claim and stimulated French interest in the Mississippi. That in turn stimulated Spanish efforts in Texas and led to the establishment of missions in East Texas in 1690, greatly accelerating European settlement of the state.