Original inhabitants of the area, now Medina County, were the Coahuiltecan people. Non-indigenous settlers to the area came from Alsace-Lorraine, Germany, Belgium and Mexico. Many family-owned businesses, farms and ranches are still owned by descendants of the non-indigenous families.
The first Spaniard to explore the area was Cabeza de Vaca in the early 1530s, some 40 years after Columbus arrived in the New World.
The city of Hondo was first settled in 1881 and incorporated in 1942. The U.S. Army built an air field in the town in 1942 to train new pilots; at one time the largest air navigation school in the world, Hondo Army Air Field trained over 14,000 navigators for service during World War II before closing in 1946.
Hondo was the scene of two bank robberies in the early 1920s. The crooks were the famed Newton Gang, the most successful outlaws in U.S. history. Both bank heists occurred the same night.
In 1930, the local Hondo Lions Club erected the now somewhat famous sign reading "This is God's Country, Don't Drive Through It Like Hell" at the city limits with the intention of slowing down those speeding while traveling through town. Later, in the 1940s the sign was changed to "This is God's Country, Please Don't Drive Through It Like Hell" to satisfy those in the town who were displeased with the tone of the old sign.  The sign has been in news and print in many magazines, including on the cover of National Geographic, and in the music video of Little Texas' song "God Blessed Texas."