Bill O'Brien was born in Fort Worth, Texas. He graduated from Abilene High School, Hardin-Simmons University, and Southwestern Seminary's School of Church music with a Master of Church Music. He was the first full-time Minister of Music at Wilshire Baptist Church. Hardin-Simmons honored him with a Doctor of Divinity degree in 1981.

O'Brien was appointed as missionary to Indonesia in 1962 where he served for two terms in the field of music and the arts, as well as teaching in the Baptist seminary and directing radio-television for Indonesian Baptists. In 1976 Bill joined the administrative staff of the Foreign Mission Board in Richmond, Virginia. His work there spanned almost fifteen years, including nine years as Executive Vice-President.

In 1991, O'Brien became the founding director of the Global Center at Samford University and missions professor at its Beeson Divinity School. Bill served on the board of directors of the Birmingham Civil Rights Institute for six years. He was president of the American Society of Missiology for the 2003-2004 term.

Since retiring in 2000, O'Brien has served as the inaugural Missions Scholar-in-Residence at Baylor's Truett Theological Seminary, and as adjunct professor at the John Leland Center for Theological Studies in Washington D.C., and at Dallas Baptist University.

O'Brien currently serves as the interim Executive Director of the Gaston Christian Center. The center serves as a home case for diverse ministries for body, mind, and spirit, including Anglo, Asian, African, and Latino congregations, a medical-dental ministry for the uninsured, and a refugee resettlement and cultural orientation ministry.

Bill has three children, six grandchildren, and three great-grandchildren. he and his wife, Charmaine, live in Dallas, Texas.