John Isbell was born on July 13, 1844, in Wallace Landing, Osage County, Missouri, the son of Zachariah Isbell and Elizabeth Wallace. Isbell’s father originally hailed from Virginia, while his mother was a native Missourian. Zachariah Isbell earned a reputation as a staunch Democrat and represented several counties in the Missouri Senate throughout his life. Census records indicate that Elizabeth Isbell died before 1850 and Zachariah remarried Amelia Moore on November 11, 1852.

Although Isbell was only sixteen when the Civil War began, one biographer recalled that he was “one of the first to take up the Union cause.” He absorbed the political principles of his father, who attended a Unionist meeting in Osage County, Missouri, and expressed "unfaltering devotion to the Union." Shortly after his eighteenth birthday, Isbell enlisted as a private in Company A of the 28th Enrolled Missouri Militia Regiment on July 29, 1862, in Linn, Missouri. He mustered into service the following day in Osage County. On September 10, 1862, Isbell received a promotion to captain and quartermaster for his regiment. While the state discharged the entire regiment between October 12 and October 20, 1862, the 28th was ordered back into service beginning May 1, 1863. Isbell’s regiment continued the cycle of discharge and return to service throughout the war. Isbell received his final discharge on November 30, 1864. One biographer asserted that Isbell “distinguished himself by faithfulness to duty and was beloved and esteemed by all those who served with and under him.”

Following his military service, Isbell likely levied his father’s position in the state senate and served as an enrolling clerk in the Missouri legislature for the 1864-65 session. At the conclusion of the legislative session, Isbell began studying medicine under Dr. Benjamin F. Burch of Washington, Missouri. Isbell remained close with the Burch family and lodged with them for a while after the war. After studying with Burch for approximately a year, Isbell enrolled at the University of Virginia School of Medicine for the 1866-67 academic year, receiving his degree that June. In 1868, he enrolled at the St. Louis Medical College, where he took a hospital and clinical course. He then moved to Kansas City, Missouri, where he practiced medicine and worked as a demonstrator of anatomy for Kansas City’s College of Physicians and Surgeons. At Burch’s request, Isbell returned to Washington and established a successful practice. Isbell’s patients deeply admired him, describing him as “a man of strong personality who readily inspires that confidence which is so important a part of successful treatment. He is kind yet firm and his visits have brought hope into many houses where gloom and despair prevail.” He also served as the local surgeon for the Missouri Pacific Railroad. He joined the local medical societies as well as the American Medical Association. In addition to his medical career, Isbell remained invested in local politics, even serving as the president of the Democratic Convention of Franklin County in 1894.

On June 13, 1877, Isbell married Sarah Belle McDonald, who went by her middle name. Belle gave birth to a daughter, Alice Maude, in September 1878. In October 1887, Belle gave birth to another daughter named Mary Mildred. Throughout their lives, the Isbells retained one or more servants of various races and nationalities. By 1900, Isbell’s mother-in-law Matilda McDonald had moved in with the family. Maude (as she was known) married Dr. Emmet P. North, and Mary married Logan H. Zintgraff, but the daughters remained close to their parents throughout their lives and frequently visited home. Members of the Isbell family were all devoted members of the Presbyterian church who regularly attended services. John Isbell died of myocarditis at his home in Washington on February 10, 1922.