The 69-year-old had a close relationship with Pope Francis and is sometimes referred to as "Italian Bergoglio", meaning the Italian version of the late pope, who was born Jorge Mario Bergoglio.
Born and raised in Rome, Cardinal Zuppi would be the first Italian pope since 1978 if he is elected.
He also has close family ties to the Vatican. His father Enrico was the editor of the Sunday supplement of the Vatican newspaper L'Osservatore Romano, while his mother's uncle, Carlo Confalonieri, was also a cardinal.
He is known as "Don Matteo", a nod to his down-to-earth persona - and the name of a popular character on Italian TV.
Italian newspaper La Repubblica described him as "a friendly and generous priest, warm in personal human contact, but also a sharp politician and a manager who is all but naive".
Here is everything you need to know about the Italian cardinal.
A continuity candidate
Cardinal Zuppi is largely seen as a candidate who would continue in Francis's progressive footsteps.
Similarly to the late pope, Cardinal Zuppi was known as a "street priest" when he lived in Buenos Aires, focusing on migrants and the poor over pomp and protocol.
He goes by his preferred name of Father Matteo, and in Bologna, sometimes uses a bicycle rather than an official car.
His progressive leaning is evident by the fact that he wrote the introduction to the Italian version of Building A Bridge, a book by American Jesuit Rev James Martin that focuses on the church's need to improve its outreach to the LGBTQ+ community.
Close ties to Community of Sant'Egidio
The Italian cardinal is closely associated with the Community of Sant'Egidio, a Catholic group based in the historic Rome district of Trastevere, where he spent most of his life as a priest.
He said in the past he "owes" his position in the church to Sant'Egidio.
The volunteer group is dedicated to helping the poor, peace-building, and prayer and is sometimes referred to as the "United Nations of Trastevere".
In the 1990s, Cardinal Zuppi played a key role in securing a peace agreement that ended a 17-year civil war in Mozambique.
His work with Sant'Egidio helped him become known for peace-making and in 2023, Cardinal Zuppi was chosen by Francis as his special envoy to Russia and Ukraine.
His role concentrated on returning children who Ukraine said had been deported to Russia or Russian-held territories, and saw him travel to Kyiv, Moscow, Beijing and Washington DC.
Inquiry into historical sex abuse
In 2022, Cardinal Zuppi became the president of the Italian bishops' conference - which gathers regularly to promote the life of the church.
One of his first acts as president was to open an inquiry on sex abuse by Catholic clergy in Italy.
The first report of the inquiry was criticised for not examining data on abuse after the year 2000.
But Cardinal Zuppi defended it, saying that analysis was not going back further because it was difficult to judge the past by today's standards.
"There is no desire to cover up anything... we are not running away from anything," he said.