When the Civil War broke out, Sayers joined the Confederate States Army's 5th Texas Regiment, a cavalry unit led by General Tom Green. He participated in the Battle of Valverde in New Mexico in February 1862, and was recommended for promotion for his bravery in capturing an artillery battery. Later that year he returned to Texas with his regiment before being sent to Louisiana, where he was wounded in the battle of Camp Bisland in April 1863. His actions during that conflict led to his promotion to major, and he became Green's chief–of–staff. Sayers was wounded again in April 1864 at the Battle of Mansfield. After Green died at the Battle of Blair's Landing, Sayers became the assistant adjutant to General Richard Taylor.

After the war ended, Sayers returned to Texas. He opened a school, simultaneously studied law and was later admitted to the Texas Bar in 1866. He entered political service in 1873, when he became a state senator in the 13th Texas Legislature. In his term, he helped reverse most of the legislation that had been passed under the Radical Republicans. After his term ended in 1875, Sayers spent three years as chairman of the Texas State Democratic Executive Committee. He presided over the state Democratic convention in both 1876 and 1878. At the 1878 convention he was nominated to be lieutenant governor under Oran M. Roberts and later won the election. In 1884, Sayers was elected to U.S. Congress, where he served until 1898. That year, he ran for governor, winning the election and taking office in early 1899. During his term in office, labor unions were exempted from antitrust laws, and blacklists were outlawed. His term saw increased spending on education, prisons, and social service institutions and outlawed railroad rebates. He also spearheaded legislation that authorized the creation of school districts. Sayers's term was noteable for the number of disasters that the state faced. The burning of the Texas State Penitentiary at Huntsville, the Brazos flood of 1899, and the Galveston hurricane of 1900. Other parts of the state suffered from a severe drought, and boll weevils caused widespread cotton destruction.

At the end of his term as governor, Sayers began to practice law in San Antonio. He became a regent of the University of Texas in 1916 and was chairman of the state Industrial Accident Board (now the Texas Workers' Compensation Commission) from 1913 to 1915, a member of the board of legal examiners from 1922 to 1926, and a member of the board of pardon advisors from 1927 until his death. He died on May 15, 1929, and was buried in Fairview Cemetery, Bastrop, Texas.