It was the first time since his election nearly a year ago that the 77-year-old pope had cancelled a public engagement and came after a very busy period for the pontiff, with a number of events outdoors in cold weather.
"Pope Francis will not go to the Roman Seminary tonight because of a slight indisposition with a slight fever," chief spokesman Father Federico Lombardi said in a statement. "His doctor has advised him to skip the planned event and rest."
The cancellation came after several weeks of hectic activities for the pope as he approaches the first anniversary of his election in two weeks.
They included meetings all last week with visiting prelates to discuss the future of the Vatican's central bureaucracy, Vatican finances, and to prepare for a major Church meeting on the family scheduled for October.
The pope also presided at two lengthy ceremonies last Saturday and Sunday to induct new cardinals into the Church.
He has been holding all of his Wednesday general audiences outdoors in St. Peter's Square to accommodate the large crowds of tens of thousands of people.
In the past, general audiences in winter were held indoors in a large hall inside the Vatican, but it holds only some 10,000 people, sometimes only a fifth of the number of people who have come to see him on recent Wednesdays
Last Wednesday's audience was held in lower temperatures and brisk winds and he rode around the square in an open vehicle.
Francis, who had part of his right lung removed when he was 21, has shown no signs of ill health since his election on March 13 last year.
The pope was to have addressed priests and men studying for the priesthood at the seminary.