“It goes against every fiber of my being to leave in the middle of my Senate term,” Mr. Isakson said in a statement on Wednesday, adding that his “health challenges are taking their toll on me, my family and my staff.”

“But I know it’s the right thing to do on behalf of my state,” Mr. Isakson added.

Mr. Isakson, who won his third term in 2016, said he had already informed Georgia’s governor, Brian Kemp, of his decision to resign on Dec. 31. He missed the last few votes before the August recess after falling in his Washington apartment and fracturing four ribs. Mr. Kemp is expected to appoint Mr. Isakson’s replacement.

Mr. Isakson said he intended to return to the Senate in September and continue advocating for Georgia and those working toward finding a cure for Parkinson’s disease. He announced in 2015 that he had received a diagnosis of Parkinson’s disease two years earlier, after visiting a neurologist about stiffness in his left arm.

“Johnny’s deep and abiding love for Georgia and this nation have animated his years of service, making him not only a first-rate legislator, but also a man of the highest integrity,” said Senator Mitch McConnell of Kentucky, the majority leader. “His humor, humility and enduring faith have made him a role model to all of us who have had the pleasure to work with him.”

Mr. Isakson is widely respected for his bipartisanship and work ethic over decades of work in Georgia and national politics, and currently chairs both the Senate Select Committee on Ethics and the Veterans’ Affairs Committee. Multiple lawmakers lamented the loss of his bipartisan barbecues where, as Senator Richard J. Durbin, Democrat of Illinois, put it, “our differences disappeared slathered in sauce.”