In his early teens Horace ran away from home and wandered as far as Cincinnati, where he found work in a tailor's shop. At eighteen he became a "mud clerk" on the river steamboat Olivia and two years later was made her pilot. The rest of his long life was passed on the Mississippi and her great tributaries. He soon was known as a "lightning pilot" - one whose courage, judgment, and knowledge of the uncharted, unmarked, ever changing river were equal to any emergency, and his services were usually required on the large boats plying between St. Louis and New Orleans. But in April 1857 he happened to be taking an "ancient tub" from Cincinnati to New Orleans when one morning a young printer, Samuel Clemens by name, invited himself into the pilot house, struck up an acquaintance, and did much of the steering for the remainder of the trip, while Bixby sat at his ease and nursed a sore foot. The rest of the episode has been recorded, though not with complete historical accuracy, in some of the most vivid pages of American prose. When Clemens received his pilot's license, September 9, 1858, Bixby took him for a while as a partner, and the two friends met again long after in 1882 and 1902.
In the years just before the Civil War Bixby was frequently engaged in the lucrative Missouri River trade, sometimes making almost $1, 800 a month. So retentive was his memory that he learned the Missouri in an incredibly short time: for his trained intelligence it was enough to see each section of the river once in daylight and once by night. During the Civil War he was pilot on the gunboat Benton and rose to be chief of the Union River Service. For two or three years he was captain and owner of a boat that made trips to Fort Benton, Montana. Occasionally, in the upper reaches of the Missouri, the boat had to stop while a herd of buffalo swam the river; at other times there were meetings, more or less exciting, with Sioux Indians. Later he was one of the owners of the Anchor Line, which operated a fleet of palatial river steamers between St. Louis and New Orleans. He himself was captain of the City of Baton Rouge. At first the line prospered; later it lost many of its boats and finally disappeared from the river. Bixby stayed on the Mississippi long after the glory of its commerce had disappeared. He entered the government service and at the age of eighty-six was commander of the snagboat Wright. At last, however, he decided that he was growing too old for active service, and two days after his decision he died suddenly at his suburban home in Maplewood, Missouri.
Bixby was of small physique but wiry and tremendously energetic.
In 1860 Bixby married Susan Weibling of New Orleans. She died in 1867, and on January 2, 1868, he married Mary, daughter of Capt. Edwin A. Sheble of St. Louis. They had three children.