Italian Archbishop Gabriele Caccia, 68, is currently the Holy See's ambassador to the United Nations in New York.
He replaces French-born Cardinal Christophe Pierre, who at age 80 is retiring as apostolic nuncio in Washington DC.
Caccia served as the Holy See's ambassador to Lebanon and the Philippines before being posted to the UN in 2019.
Ordained a priest in Milan in 1983, Caccia later served as "assessor" in the Vatican secretariat of state, a key administrative post in the Holy See's most important office.
He inherits a complicated and consequential dossier on both the US church and state fronts.
Pierre's tenure as ambassador was notable for clear signs of friction between the leadership of the US Conference of Catholic Bishops, which tends to skew conservative, and the more progressive priorities of Pope Francis' pontificate.
The relationship with the US and its church is crucial for the Holy See, not least because US Catholics are the most generous donors to the Holy See's coffers.
Leo, history's first US-born pontiff, is well aware of the dynamic, having served as Francis' point man on bishop nominations for two years before his 2025 election.
Leo has emphasised a message of pacification and unity in the church.
Trump's first administration clashed with Francis especially on migration, and that tension has continued in Leo's pontificate and the second Trump term.
Leo has repeatedly insisted that the US administration respect the human dignity of migrants, while acknowledging its right to its borders.
More recently, Leo has expressed "profound concern" about the US-Israeli war in Iran and urged both sides to "stop the spiral of violence before it becomes an irreparable abyss".
In comments last Sunday, Leo called for the resumption of diplomacy.
Weapons, he said, only sow "destruction, pain and death".
The Holy See has a tradition of diplomatic neutrality although Leo has spoken out strongly against the humanitarian toll of Israel's military action in the Gaza Strip and Russia's invasion of Ukraine.
The current president of the US conference, Archbishop Paul S Coakley, welcomed Caccia's appointment and offered the US hierarchy's "warmest welcome and our prayerful support".
