Davis, 53, had said in December he would not seek a fifth term. His resignation was effective immediately.
"Recently, a family health issue has developed that will demand significantly more of my time to assist," Davis said in a statement posted on his official Web site. "As a result, I cannot continue to effectively fulfill my obligations to both my office and my family. Family must and will come first."
Davis thanked his constituents "for the honor of serving as their congressman over the last eight years" and noted he has worked alongside "great men and women in the Congress in both parties."
"I am grateful to have been blessed by being a part of this great institution," he concluded.
Roll Call said Kentucky Gov. Steven Beshear, a Republican, is expected to schedule a special election the same day as the general election, Nov. 6, to select someone to serve out the remainder of Davis' term.
Thomas Massie is the Tea Party-backed GOP nominee for the heavily Republican 4th District in eastern Kentucky.