With virtually all the results counted, Mr Fillon won Sunday’s run-off with nearly 67% of the vote.
Mr Fillon promised to build a fairer society, saying France wants “truth and it wants action”.
He is likely to face a Socialist candidate and the far-right’s Marine Le Pen in next April’s election.
Mr Juppe, the more moderate candidate, congratulated Mr Fillon on his “large victory” and pledged to support him in his bid to become president.
Francois Fillon was the man to beat going into this run-off vote, and his team knew it.
Shortly after polls closed, they were already celebrating at his party headquarters, as the first partial results came in. Within hours, it was confirmed. Mr Fillon had won two-thirds of the vote; a stunning victory for the candidate once seen as the ‘third man’ in the contest.
Alain Juppe appeared in front of his own, determined supporters, to concede the contest. He gave a small smile to the crowds chanting his name and told them he was ending the contest as he began it: “A free man, who didn’t betray who he was or what he thought.”
The job for Mr Fillon now is to unite his party after this unprecedented primary battle, and prepare to take on the governing Socialist party – and the far-right leader Marine Le Pen – in presidential elections next year.
With votes from 9,713 of the 10,229 polling stations counted, Mr Fillon had won 66.6% while Mr Juppe had 33.4%.
As the result of the Republican party primary became clear, Mr Fillon told his supporters he would work for change.
“If the French people entrust me with their confidence,” he said, “I will try to respect that contract and condcut myself with dignity.”
“I will take up an unusual challenge for France,” he went on to say. “To tell the truth and completely change its software.”
Mr Fillon had been widely expected to win the race, after securing 44% of the vote in the first round a week ago that saw former President Nicolas Sarkozy knocked out.
A former prime minister under Mr Sarkozy, the 62-year-old is a Catholic who is seen as a traditionalist on issues such as abortion and gay marriage.
He is proposing dramatic economic reforms that include slashing 500,000 public jobs, ending the 35-hour week, raising the retirement age and scrapping the wealth tax.
Mr Juppe, also a former prime minister, had initially been seen as the favorite to win the race, but struggled against Mr Fillon’s strong performances in the primary debates.
Now the spotlight falls on the Socialist party, and whether the deeply unpopular President Francois Hollande will stand again in his party’s primaries in January. He is expected to announce his decision in the coming days.
Prime Minister Manuel Valls said on Sunday that he would not rule out running against Mr Hollande in the primary, telling the Journal du Dimanche he wanted to dispel the idea “that the left has no chance” of retaining power.
Meanwhile, Emmanuel Macron, the 38-year-old former economy minister and protege of Mr Hollande, has already announced plans to stand in the presidential election as a centrist independent.