
Unfortunately for Arthur, a serious health problem prevented him from capitalizing on his political success. Less than a year after assuming the presidency, Arthur was diagnosed with Bright’s disease, a fatal kidney condition. According to author Zachary Karabell in his American Presidents Series biography of the 21st President, Arthur’s ailment, would probably be diagnosed as glomerulonephritis today. Karabell writes that the disease “made it difficult for his nephrons to rid his body of toxins. His blood and body were slowly being poisoned by his own digestion.”

Among the symptoms of this condition was great fatigue. Many perceived Arthur as lazy, and a contemporaty cartoon, entitled "nightcaps of the round table" portrayed Arthur and his cabinet asleep. But this lethargy was very likely the product of his poor health. To exacerbate matters, Arthur was still grieving the death of his wife Ellen, who passed away in January of 1880 at the age of 42 from pneumonia. After becoming president, Arthur paid for a stained glass window to be put in St. John's Episcopal Church, where his wife had been a devout parishioner. It was said that Arthur could see the church from his office. The window was dedicated to Ellen. He had it installed where he could view it at night, as the lights were kept on within the church. In addition, he ordered fresh flowers placed daily before her portrait in the White House.
Arthur's rich diet did not help his condition. It is said that he enjoyed fine wines and after-dinner liqueurs. His love for rich foods caused his weight to increase, 220 pounds.
Arthur attempted to keep his condition private, but by 1883 rumors of his illness became public. His lack of energy made it difficult for him to keep up with the demands of the presidency. In an effort to rejuvenate his health, Arthur and some political friends traveled to Florida in April 1883. The vacation had the opposite effect to what Arthur had intended. He suffered from intense pain before returning to the capitol. Later that year, on the advice of Missouri Senator George Graham Vest, Arthur visited Yellowstone National Park. Reporters accompanied the presidential party, which included General Philip Sheridan and Secretary of War Robert Todd Lincoln. The presidential tour helped to publicize the new National Park system. More important to Arthur, the trip seemed to improve Arthur's health and he returned to Washington refreshed after two months of travel.

Perhaps if he had been healthier and more energetic, Arthur might have salvaged his political career and ran for re-election. As the 1884 presidential election approached, Arthur was interested in another term as President, but James G. Blaine was considered the favorite for the Republican nomination. Neither faction of the Republican party was prepared to give Arthur their support. The former Garfield faction supported Blaine, while Stalwarts were divided, with some backing Arthur, while others supported Senator John A. Logan of Illinois. Reform-minded Republicans appreciated Arthur for endorsing civil service reform, but they were still not confident in his reform credentials, and many of them backed Senator George F. Edmunds of Vermont, who had been a long-time supporter of their cause.
By the time the convention began in June, Arthur realized that he would not win the nomination, though he still maintained efforts to conceal the true state of his health. At the convention Blaine led on the first ballot, and captured the nomination on the fourth ballot. Arthur telegraphed his congratulations to Blaine and was gracious in defeat. He played no role in the 1884 campaign, and Blaine would later blame Arthur's lack of campaigning in New York for his loss that November to Democrat Grover Cleveland.
Arthur left office in 1885 and returned to his New York City home. New York Stalwarts had approached him to run for United States Senate, but he declined, and returned to his old law practice at Arthur, Knevals & Ransom. His poor health limited his activity with the firm, and he was often too ill to leave his house. Arthur made few public appearances.
After summering in New London, Connecticut, in 1886, Arthur returned home to New York feeling quite ill. On November 16, apparently knowing that the end was near, Arthur ordered nearly all of his papers, both personal and official, burned. The next morning, Arthur suffered a cerebral hemorrhage and never regained consciousness. He died the following day, November 18, 1886 at the age of 57.