He replaces the hugely respected Lakhdar Brahimi, who resigned in May after two rounds of peace talks collapsed and as the conflict escalated into a fourth year, killing more than 162,000 people.
UN chief Ban Ki-moon confirmed the appointment of the special representative and his Egyptian deputy, urging the divided Security Council and Syrian parties to work closely with him.
Ban has frequently criticised animosity on the Council between Western powers and Russia, a close ally of Damascus, which has all but paralysed an international response to the crisis.
He said the Arab League had recommended Egyptian diplomat and former deputy foreign minister Ramzy Ezzeldin Ramzy for the deputy job, but that both appointments had been made by him as UN chief.
Brahimi, a seasoned Algerian diplomat, was joint representative of both the United Nations and Arab League.
De Mistura, who has served previously in Iraq and Afghanistan, inherits a job many consider flat-out impossible.
Questioned about whether the Italian-Swede, now the third envoy to the crisis, could bring anything new to the table, Ban acknowledged it was a tough job.
The appointment was welcomed by US Secretary of State John Kerry and British Foreign Secretary William Hague, as well as the Syrian opposition.
Kerry called de Mistura "a distinguished diplomat who brings a wealth of experience."
"We applaud his readiness to continue the important mission of trying to bring an end to the suffering and brutal violence inside Syria and to forge a path toward a political transition," Kerry added.