The pope, who has attracted the ire of US President Donald Trump after becoming more outspoken against war and despotism, was also due to visit a high-security prison that human rights groups say holds political prisoners in abusive conditions.
Leo, the first US pope, started the day by flying about 300km from Malabo, on Bioko Island in the Gulf of Guinea, to Mongomo, on the eastern border with Gabon on the edge of the Congo Basin rainforest.
At a mass in the largest religious structure in Central Africa, the pontiff urged Equatorial Guineans "to serve the common good rather than private interests, bridging the gap between the privileged and the disadvantaged".
The Pope, who has revealed a forceful new speaking style during the Africa tour, also decried poor treatment of "prisoners who are often forced to live in troubling hygienic and sanitary conditions".
The Vatican said roughly 100,000 people had gathered inside and outside the Basilica of the Immaculate Conception 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 Guinean flags.
Leo's trip to Mongomo was the first of three flights to three cities on a day of whirlwind travel that will also take him to Bata, on the western coast.
Equatorial Guinea, run since 1979 by President Teodoro Obiang Nguema Mbasogo, the world's longest-serving president, has been widely criticised as one of the most repressive countries in the region.
Obiang, who oversaw a now-declining oil boom that began in the 1990s, denies allegations of human rights abuses and corruption.
He was present with Leo in Mongomo, appearing with the pope to greet crowds, as was his son, Vice President Teodoro Nguema Obiang Mangue.
More than 70 per cent of Equatorial Guinea's population of 1.8 million identify as Catholic.
Leo is at the end of one of the most complicated overseas tours ever arranged for a pontiff.
He has traversed nearly 18,000km across 18 flights to 11 cities in four countries.
Later on Wednesday, the Pope was scheduled to visit a high-security detention centre in Bata.
Amnesty International says it is one of three facilities in the country where detainees are regularly held for years without access to lawyers.
Leo will also pray in Bata at the site of a series of explosions in 2021 at a military barracks that killed more than 100 people.
