The court increased Stephan Schmidheiny's prison sentence in absentia to 18 years from 16 years when he was first convicted last year and ordered him to pay tens of millions of euros (dollars) to local authorities and victims' families.
Campaigners immediately hailed the verdict as an important landmark in the fight against asbestos, which is now banned by the European Union but is still widely used in the developing world.
Italy's National Asbestos Observatory said the sentence "encourages the battle of victims and relatives and honest people for a better world without asbestos and without a thirst for profit".
Bruno Pesce, head of the Association of Families of Asbestos Victims, who was present at the hearing, said the sentence was "a precedent".
Speaking to news channel Sky Tg 24, another campaigner Nicola Pondrano, said the company's management had been "not just irresponsible but really criminal because they did not give workers basic information like the fact that asbestos is cancerogenic".
Eternit had caused "a real massacre" in the towns in which it had plants, Pondrano said.
He said he hoped the billionaire would begin paying out compensation "starting tomorrow" and argued that the Italian state could begin contributing if this was not possible.
Schmidheiny's defence team said it would appeal the ruling in Italy's highest court, with lawyer Astolfo Di Amato saying he was outraged by a verdict likely to put others off investing in Italy.
The tycoon is the former owner of Italian company Eternit, which made construction material using asbestos in the 1970s and 1980s, and he was taken to court by a group of former employees.
Referred to by Forbes magazine as the "Bill Gates of Switzerland" for his philanthropy, Schmidheiny was found by the appeals court to have caused "a permanent health and environment catastrophe".
Prosecutor Raffaele Guariniello said the verdict gave "everyone in Italy and the whole world the right to dream that justice can and must be done."
The case against Belgian baron Jean-Louis Marie Ghislain de Cartier de Marchienne, a major Eternit shareholder who was also being tried in absentia, was dropped because he died last month at the age of 92.
The town of Casale Monferrato, one of the worst hit by asbestos-related cases, was awarded 30.9 million euros in damages while the Piedmont region, where the largest Eternit factory was located, was awarded 20 million euros.
Relatives of victims had gathered at the court waving yellow placards reading "Justice for Eternit Massacre", and some burst into tears as the verdict was read out.
The mayor of Casale Monferrato, Giorgio Demezzi, said he was "satisfied with the compensation" which he said would go towards cleaning up contaminated sites in the town.
Lawyers for Schmidheiny had argued that he did not have a direct responsibility in the management of Eternit Italy.
Eternit went bankrupt six years before asbestos was banned in Italy in 1992.
The first trial began in 2009 after a five-year investigation and is the biggest of its kind against a multinational for asbestos-related deaths.
Asbestos, which was banned in Europe in 2005, but is still widely used in the developing world, had been used mainly as building insulation for its sound absorption and resistance to fire, heat and electrical damage.
The inhalation of asbestos fibres can cause lung inflammation and cancer, and symptoms can take up to 20 years to manifest after exposure.