The first American head of the Catholic Church is expected to draw large crowds on the trip from Saturday to June 12, with stops in Madrid, Montserrat Monastery and the Canary Islands, a Spanish archipelago off the west coast of Africa.
Leo, who angered US President Donald Trump by criticising his anti-immigration policies, will meet with migrants and organisations dedicated to helping them on the last stop of his tour.
The situation faced by migrants is close to the Pope's heart, the Vatican's press office director Matteo Bruni said.
"These are people, and their stories must touch us."
Leo, who has adopted a more forceful tone against the direction of global leadership in recent months, is scheduled to give more than 20 speeches, becoming the first Pope to address the Spanish parliament.
He is likely to decry the wars raging around the world and urge dialogue to overcome growing political and social polarisation, Bruni said.
Leo spent decades as a missionary and bishop in Peru before becoming Pope in May 2025, and will speak Spanish throughout most of the trip.
But when he meets migrants on the island of Tenerife, he expects to speak French as many have come from Francophone Africa.
In sharp contrast to many leading Western powers, not least Trump's US, Prime Minister Pedro Sanchez's Socialist government has opened a mass amnesty program, allowing an estimated 500,000 immigrants to apply for legal status.
More than 3000 people died in 2025 trying to reach the Canary Islands, often in makeshift dinghies, according to the NGO Caminando Fronteras.
Sanchez has been lauded abroad by some for criticising Trump, but at home has been under heavy pressure from a string of corruption allegations against his party.
After landing in Madrid on Saturday morning, Leo will meet King Felipe and Queen Letizia at the Royal Palace and address diplomats and civil leaders.
He will then meet young people in the square outside the Santiago Bernabeu Stadium, home to the Real Madrid soccer club, and visit a Catholic charity for the homeless.
