Attending the gathering are some 45 leaders, including German Chancellor Angela Merkel, Spanish Prime Minister Mariano Rajoy, Brazilian President Dilma Rousseff, Cuban leader Raul Castro as well as European Council President Herman Van Rompuy and European Commission President Jose Manuel Barroso.
Although the two blocs have met seven times, it is the 27-member European Union's first summit with the Community of Latin American and Caribbean States (CELAC, its Spanish-language acronym).
Set up in Caracas in December 2011 at the behest of Venezuelan President Hugo Chavez, CELAC groups all American nations except the United States and Canada and aims to boost regional trade and institutional cooperation,.
Chavez, who is convalescing from cancer surgery in Cuba, will not attend the weekend gathering.
Monday, CELAC leaders will hold their own summit here, with Cuba taking over the chairmanship from Chile for one year.
The meeting will seal Cuba's full regional reintegration and mark a major diplomatic coup for President Castro, whose communist-ruled country is still reeling from a 50-year-old crippling US trade embargo.
The 33 CELAC leaders hope to overcome their ideological and economic differences to foster greater regional integration.
"Our efforts (in this area) have not lived up to that is needed and what Latin America deserves," Chilean President Sebastian Pinera conceded.
Shortly before Castro landed here Friday, about 200 people protested both for and against Havana.
An estimated 100 demonstrators massed outside the Cuban embassy, heeding a call by Chile's ruling party, the conservative Independent Democratic Union, or UDI, to demonstrate against the Castro`s presence in the Chilean capital.
The UDI accuses Castro of harboring the murderers of their party's founder, Jaime Guzman, a senator who was killed in 1991 by the nearly extinct radical leftist group Patriotic Front of Manuel Rodriguez.
The UDI president, along with other lawmakers, also came to the embassy to deliver a letter demanding to know the whereabouts in Cuba of those they allege killed Guzman: Ricardo Poblete, and three other accomplices.
However, the lawmakers were denied entry and then threw the letter into the garden.
Another 100 demonstrators, from a "Group of Solidarity with Cuba," also gathered near the embassy to show support for Cuba .
Ahead of the EU-CELAC summit, Pinera, the host, said the meeting aimed to "to seal a new strategic alliance for development and more open markets."
"It will be the first timethat Latin America will speak with one voice" with Europe, Chilean Foreign Minister Alfredo Moreno said recently.
The EU is the biggest outside investor in Latin America, with 3 percent of the direct foreign investment in CELAC or $385 billion in 2010.
Thursday, Van Rompuy and Barroso attended a EU-Brazil summit with Brazilian President Dilma Rousseff in Brasilia.
The two sides called for the speedy conclusion of a free trade pact between the EU and the South American trading bloc Mercosur.
Negotiations over the pact have so far stumbled over differences on agriculture -- notably Europe's subsidies to its farmers, which undermine South America's efforts to sell its own products.
Meanwhile, a parallel Summit of the Peoples got under way here Friday with a march of 1,000 leftists protesting capitalist economic policies.
The march turned violent when hooded demonstrators tore down traffic lights and shops' shutters in central Santiago, prompting police to intervene with water cannons ans tear gas.
At least five protesters were arrested.
The two-day counter-summit brings together representatives of more than 400 social movements from across Latin America and Europe.