Widely derided as one of the most repressive countries in the region, Spanish-speaking Equatorial Guinea has been run since 1979 by President Teodoro Obiang Nguema Mbasogo, the world's longest-serving president.
It has enjoyed warm ties with the US in part because of its oil riches.
Leo, the first US pope who has debuted a forceful new speaking style while in Africa, began the day by denouncing wealth inequality during a Mass in the largest religious structure in Central Africa, a church in the town of Mongomo, situated at the edge of the Congo Basin rainforest.
He then visited a prison in the city of Bata, a facility where detainees are regularly held for years without access to lawyers, Amnesty International says.
Leo listened to several testimonies from prisoners who had gathered in a yard inside the facility. As he made remarks it began to rain, but the detainees remained standing outside.
The Pope asked that "every effort" be made to allow detainees the opportunity to study and work during their confinement.
As he was leaving, and as Justice Minister Reginaldo Biyogo Mba Ndong Anguesomo remained on stage, prisoners began jumping up and down in the rain and shouting: "Freedom, freedom!"
Equatorial Guinea has long dismissed accusations of human rights abuses. Before Leo spoke at the prison in Bata, Biyogo said the country treats prisoners fairly in accordance with United Nations standards.
"We are committed to guaranteeing human rights, fundamental rights, and citizenship," he said.
Obiang's government last year struck a deal with the Trump administration to accept deportees from other countries, one in a series of such arrangements in Africa that have drawn criticism from immigration lawyers and advocates.
Activists were hoping Leo would draw attention to the deportees sent from the US to Equatorial Guinea.
A group of 70 NGOs published an open letter on Monday calling on Leo to push for "fair, humane and lawful treatment" of the deportees, saying they were being pressured to return to their home countries.
Leo, who has attracted the ire of US President Donald Trump after becoming more outspoken against war and despotism, did not publicly address the plight of the deportees while in Equatorial Guinea or in Cameroon, the first stop on his tour and another country that has received them.
During the Mass on Wednesday morning at the Basilica of the Immaculate Conception in Mongomo, Leo urged Equatorial Guineans "to serve the common good rather than private interests, bridging the gap between the privileged and the disadvantaged".
The Vatican said roughly 100,000 people had gathered inside and outside the basilica to see Leo on Wednesday, pressing in around a colonnade modelled after St Peter's Square in Rome.
They danced and screamed as his white 'popemobile' arrived. Organisers released gold, white, green and red smoke in the air, nodding to the colours of the Vatican and Equatorial Guinea flags.
More than 70 per cent of Equatorial Guinea's population of 1.8 million identify as Catholic. Leo, who is the first pope to visit since 1982, is at the end of one of the most complicated overseas tours ever arranged for a pontiff. He has traversed nearly 18,000 km across 18 flights to 11 cities in four countries.
