As part of his first trip to the area that was once part of the Ottoman Empire, the pope visited the Mother Teresa Memorial House, which stands on the site of the former Church of the Sacred Heart.
Mother Teresa was canonized as a saint in 2016 by Francis, 19 years after her death. The Catholic nun devoted her life to helping the poor in India.
"God, Father of mercy and all goodness, we thank you for giving us the life and the charisma of Saint Mother Teresa," the pontiff said during prayers Tuesday. "In your boundless providence, you called her to bear witness to your love among the poorest of the poor in India and throughout the world.
"She was able to do much good to those in greatest need, for she saw in every man and woman the face of your Son. Docile to your spirit, she became the prayerful cry of the poor and of all those who hunger and thirst for justice."
During the historic visit, the pope also praised North Macedonia as a bridge between east and west and encouraged it to engage more with European institutions now that a decades-long dispute with Greece over its name has been settled. In February, North Macedonia was admitted to NATO as a direct result of the settlement.
About 15,000 people attended Tuesday's mass at Macedonia Square. The visit to Skopje comes at the end of a three-day tour that also took Francis to Bulgaria.
Mother Teresa was born Agnes Gonxha Bojaxhiu and her parents were ethnic Albanians and devout Catholics. She became a missionary nun at 17 and joined the Sisters of Loreto in Ireland, which would lead her to teach in Calcutta, India.