"I leave full of hope. We are warriors, full of light and faith in Christ to keep battling and conquering," Chavez said shortly before boarding the flight to Havana.
"I hope to be back soon," said Chavez, who pumped a fist in the air as he walked up the steps to the plane.
The 58-year-old socialist leader is facing his fourth operation since mid-2011 for a third recurrence of an undisclosed form of cancer in the pelvic area.
Chavez stunned Venezuelans over the weekend with his announcement that more malignant cells had been found, despite twice declaring himself completely cured in the past.
He won a presidential election in October and is due to start a new six-year term on January 10. Chavez's departure from office, either before or after that date, would trigger a vote within 30 days.
It would also mark the end of an era given his flamboyant leadership of Latin America's hard left and self-appointed role as Washington's main provocateur in the region.
In a speech to the nation on Saturday night, Chavez named Vice President and Foreign Minister Nicolas Maduro to take over should he become incapacitated. He also urged supporters to vote for Maduro in the event of an election.
"I trust completely in my soldiers," Chavez said, dressed in a blue-and-white track suit, during the swearing-in of a new defense minister before his departure. "The republic and the revolution are in good hands."
The naming of Maduro and swearing-in of a new defense minister appeared to be Chavez's way of trying to leave the house in good order.
Ministers were once again trying to keep Venezuelans calm despite frenzied speculation.
"We are still working the same, following the instructions of the president who remains the president of the republic," Finance Minister Jorge Giordani told Reuters.
But the health saga has once again eclipsed major national issues such as state elections on Sunday, a widely respected devaluation of the bolivar currency, and a proposed amnesty for Chavez's jailed and exiled political foes.
Opposition leaders say Venezuela is entering potentially dangerous waters and a temporary president should be named during Chavez's absence, as allowed by the constitution.
While sympathizing with Chavez and wishing him good health, the opposition has criticized the secrecy around medical details and his snubbing of local doctors in favor of Cuba.
"Hiding information for partial gain, without taking into account the national interest, is not a democratic procedure, it does not give good results," said Ramon Guillermo Aveledo, the leader of Venezuela's Democratic Unity coalition.
Information Minister Ernesto Villegas said Chavez's Havana-bound plane had left Caracas at about 1:30 a.m. (0600 GMT).
Venezuela's global bonds, among the most traded hard-currency emerging market papers, are volatile on Chavez's health, with downturns generally driving up prices. On Monday, the benchmark dollar-denominated bond maturing in 2027 rose 2.31 percent or 2.000 points to bid 100.750.
Chavez's health also has major implications for the region. A handful of Latin American and Caribbean neighbors - from Cuba and Nicaragua to Bolivia and Ecuador - have come to depend on his oil-fueled largesse to bolster their fragile economies.
Many analysts fear that despite Chavez's anointment of Maduro, his "Chavismo" movement could disintegrate without him, especially given rumored rivalries among the main players.
"We remain of the view there could very well be no Chavismo without Chavez," Goldman Sachs analyst Alberto Ramos said.
"No other senior figure has yet to show the capacity to replicate the president's charisma and unique connection with voters. Therefore, were President Chavez forced to leave the political scene due to health reasons, the Chavismo movement could eventually weaken, leading to a possibly noisy, and not necessarily short, political transition in Venezuela."
Among the senior "Chavistas", Maduro - a 50-year-old former bus driver and union leader - is widely viewed as the most popular, thanks to his affable manner and close ties to Chavez.
While his humble background appeals to the Chavez's working class supporters, Maduro's six years as foreign minister have also given him good contacts in China, Russia and other influential nations. He has an easygoing style but is a firm believer in Chavez's leftist policies and has often led fierce criticism of the United States.
If a new election were needed, the opposition could be in its best position to win since Chavez took power in 1999. Many voters have overlooked the government's failings because of their deep emotional connection with the president.
Henrique Capriles, a state governor, lost to Chavez in the October, but he received 44 percent of ballots cast, a record 6.5 million votes for the opposition, and could run again.