The 83-year-old pontiff, who suffers from Parkinson's disease, held up rather well throughout his two and a half hours in the public's eye, although near the end of the canonization Mass he began heavily slurring his words and let German Cardinal Walter Kasper read three paragraphs in German.
John Paul declared three missionaries to be saints: Daniele Comboni, an Italian; Arnold Janssen, a German; and Josef Freinademetz, an Austrian.
Comboni journeyed as a young priest to Africa and founded an order of missionaries named after him. He died in Khartoum, Sudan, in 1881.
Janssen, who died in 1909, began working as a priest in Germany. Later he began the Divine Word Missionaries, whose early ranks included Freinademetz.
Freinademetz, born in what now is Italy's South Tyrol, died in 1908 after contracting typhoid in China while caring for patients.
The pope chanted several prayers in a loud, clear voice, greeted a long line of VIPs one by one and watched with attention as African and Asian dancers performed in honor of the three saints.
After the ceremony, John Paul was helped into the white open-topped vehicle dubbed the "popemobile" for a 10-minute spin around the cobblestone square.
Firmly gripping a safety bar with one hand, John Paul alternately waved and gave his blessing with the other hand as faithful applauded and snapped photos.
Earlier in the week, some unusually frank assessments by churchmen, including several cardinals, heightened alarm over his deteriorating condition.
One cardinal, Christoph Schoenborn of Austria, said John Paul was dying — a shocking departure from the reserve that prelates had over the last few years in discussing the pope's condition.
Until relatively recently, top churchmen wouldn't even publicly acknowledge that the pontiff had Parkinson's, despite evident symptoms like hand tremors, stiff facial muscles and stooped posture.
Sunday's canonization was the 50th such ceremony John Paul II has led since becoming pontiff in 1978. In all, he has raised to sainthood 476 faithful, new role models he hopes will help shore up the faith of Catholics.
John Paul said the ceremony highlighted the need "in these times" for the "enthusiasm and apostolic passion" like that shown by the new saints.
"Every Christian is sent out on a mission," the pope said, urging rank-and-file faithful to be "authentic witnesses of Christ."
John Paul marks 25 years in the papacy this month. Besides several anniversary events, the pope has several other stamina-taxing appointments coming up, including the Oct. 19 beatification of Mother Teresa and an Oct. 21 ceremony to give the Church more cardinals, the electors who will eventually chose John Paul's successor.
On Sunday, the pope spoke with anticipation of a pilgrimage he will make Tuesday to Pompeii, near Naples.