The trip will see the head of the Catholic Church travel to Kenya and Uganda, both victim of Islamist militant attacks, and the Central African Republic, a country torn apart by Muslim-Christian strife.
In a speech delivered shortly after arriving in Kenya, the pope urged world leaders to pursue responsible economic development and to protect nature for future generations.
Francis is expected to address climate issues when he visits the regional U.N. headquarters in Nairobi on Thursday.
"To the extent that our societies experience divisions, whether ethnic, religious or economic, all men and women of good will are called to work for reconciliation and peace, forgiveness and healing," the pope said in Nairobi.
He was speaking at State House, the official residence of President Uhuru Kenyatta, who is a Catholic along with about 30 percent of Kenya's 45 million people. As the pope drove into Nairobi from airport, thousands lined the roads to greet him.
Africa's Catholic Church is expanding quickly, with the number of faithful expected to more than double to half a billion in 2050. The number of Muslims on the continent is also forecast to rise by about the same amount to 670 million.
At State House, the pope called for responsible development in Africa and elsewhere. One of his first actions in Kenya was to plant a tree on the State House grounds.
"The grave environmental crisis facing our world demands an ever greater sensitivity to the relationship between human beings and nature," he said. "We have a responsibility to pass on the beauty of nature in its integrity to the future generations."
Millions of Christians - Catholics and otherwise - are expected to turn out for public celebrations of Masses during the tour, presenting a challenge for national security forces to keep the pontiff and the vast crowds safe.
Kenya has suffered a spate of attacks by Somalia's Islamist group al Shabaab in the past two years that have killed hundreds of people, including the 2013 raid on a Nairobi shopping mall that killed 67. Kenya has also been plagued by ethnic tensions.
"Recent events around the world have indeed taught us that we must do even more to bring unity and understanding between faiths, between ethnicities, between races, but also between nations," Kenyatta said at State House.
Thousands of police have been deployed in Nairobi and officers will also be out in force in the Ugandan capital Kampala, which the pope visits next.
Potentially the most hazardous stop may be the third in the Central African Republic. Dozens of people have been killed there since September in violence between mostly Muslim Seleka rebels and Christian anti-balaka militias.
The pope brushed off security worries, telling reporters on his flight: "The only thing I'm concerned about is the mosquitoes. Did you bring your spray?"
