Leo travelled to the western Cameroon city of Bamenda, where jubilant Cameroonians clogged the roads, blowing horns and dancing to welcome him.
They were overjoyed that a pope had come so far to see them and put a global spotlight on the violence that has traumatised this region for nearly a decade.
Leo presided over a peace meeting on Thursday involving a Mankon traditional chief, a Presbyterian moderator, an imam and a Catholic nun.
The aim was to highlight the interfaith movement that has been seeking to end the conflict and care for its many victims.
In his remarks in the St Joseph Cathedral, on land donated by the Mankon, Leo praised the peace movement and warned against allowing religion to enter conflicts.
It's a theme he has been echoing amid the US-Israeli war in Iran and the religious justifications for it by US officials.
"Blessed are the peacemakers!" he said.
"But woe to those who manipulate religion and the very name of God for their own military, economic and political gain, dragging that which is sacred into darkness and filth."
He called for a "decisive change of course" that led away from conflict and the exploitation of the land and its people for military or economic gain.
"The world is being ravaged by a handful of tyrants, yet it is held together by a multitude of supportive brothers and sisters!"
It was not immediately clear if any of the separatist fighters, who announced a three-day pause in fighting to allow the pope safe passage, would attend.
The Pope is also set to celebrate a mass for the people of Bamenda, near Cameroon's western border with Nigeria, later on Thursday before returning to the capital Yaounde.
The conflict in Cameroon's two Anglophone regions is rooted in Cameroon's colonial history, when the country was divided between France and Britain after World War I.
English-speaking regions later joined French Cameroon in a 1961 UN-backed vote, but separatists say they have since been politically and economically marginalised.
In 2017, English-speaking separatists launched a rebellion with the stated goal of breaking away from the French-speaking majority and establishing an independent state.
The conflict has killed more than 6000 people and displaced over 600,000 others, according to the International Crisis Group.
"Those who rob your land of its resources generally invest much of the profit in weapons, thus perpetuating an endless cycle of destabilisation and death," Leo said.
"It is a world turned upside down, an exploitation of God's creation that must be denounced and rejected by every honest conscience."
On the eve of Leo's arrival, separatist fighters announced a three-day pause in fighting.
Though the number of deadly attacks by separatists has decreased in recent years, the conflict shows no sign of resolution.
Peace talks with international mediators have stalled, with both sides accusing each other of acting in bad faith.
