Blalock, co-developer of the “blue baby” operation, was born in Culloden, Georgia. He received his A.B. in 1918 from the University of Georgia and his M.D. in 1922 from the Johns Hopkins University School of Medicine. Blalock continued at The Johns Hopkins Hospital as an intern in urology, assistant resident in surgery, and externe in otolaryngology.
In 1925, Blalock became the first chief resident in surgery at Vanderbilt University Hospital, and later joined the faculty of the Vanderbilt University School of Medicine, where he did pioneering work on the nature and treatment of hemorrhagic and traumatic shock. He demonstrated that surgical shock resulted primarily from the loss of blood and he encouraged the use of plasma or whole-blood transfusions as treatment following the onset of shock. This work is credited with saving the lives of many casualties during World War II.
He returned to Johns Hopkins in 1941 as professor and director of surgery at the Johns Hopkins University School of Medicine and surgeon-in-chief of the hospital, positions he held until his retirement in 1964.
In 1944, Blalock collaborated with Helen Taussig and Vivien Thomas to develop the "blue baby" operation, a means to improve the flow of oxygen into the blood of babies born with a heart condition called Tetralogy of Fallot. The procedure connected one of the heart's major arteries with another feeding into the lungs. It not only helped save the lives of thousands of children around the world but also opened the door to now-familiar procedures like coronary bypass surgery.
While at Johns Hopkins, Blalock worked for the establishment of the Children's Medical and Surgical Center. He received numerous awards, including the Lasker Award, for his outstanding surgical contributions. He was nominated several times for the Nobel Prize in medicine. In 1964, the clinical science building was renamed in his honor at the 75th anniversary celebration of The Johns Hopkins Hospital.