Supporters prepared to gather in city squares across the South American country, shocked and saddened by the news from the 58-year-old socialist leader, who made the announcement in a late-night broadcast on Saturday from the presidential palace.
In the clearest indicator yet that Chavez's health problems could spell an end to his tumultuous years at the helm of the OPEC nation, he said supporters should vote for Vice President Nicolas Maduro if a new election had to be held.
"It is absolutely necessary, absolutely essential, that I undergo a new surgical intervention," the president said in his speech, flanked by ashen-faced ministers.
"With God's will, like on the previous occasions, we will come out of this victorious. I have complete faith in that."
His departure would trigger an election and mark the end of an era for the Latin American left, depriving them of one of their most acerbic voices.
A clutch of nations in the region, from Cuba and Nicaragua to Bolivia and Ecuador, depend on Chavez's oil-fuelled generosity to bolster their fragile economies.
An unruly transition from Chavez's highly centralized rule could also raise the spectre of political instability in Venezuela, which holds the world's largest crude oil reserves.
The president's allies lack the charisma that has made him one of the world's most recognizable leaders - and most fierce critics of Washington - and may struggle to control his unwieldy coalition of military leaders and leftist activists.
Among them, though, Maduro - a 50-year-old, moustachioed former bus driver and union leader - is widely viewed as the most popular among Venezuelans thanks to his affable manner, humble background and close relationship with Chavez.
Speculation about Chavez's health had grown during a three-week absence from public view that culminated in his latest trip for medical tests in Cuba - where he has undergone three cancer operations since June 2011.
He returned to Venezuela on Friday after those tests, and is due to have the operation in Cuba in the next few days.
Chavez said he had rejected the advice of his medical team to have the surgery sooner, on Friday or this weekend, telling them he needed to fly back to Venezuela to seek the permission of lawmakers to return for the operation.
"I decided to come, making an additional effort, in truth, because the pain is not insignificant," Chavez said.
The president's return to Cuba may mark the start of another lengthy period of silence from government officials, combined with furious rumours over what political changes might be in store and what Chavez's actual condition is.
He has never said what type of cancer he is suffering from, though when initially diagnosed in mid-2011, the government said Chavez's problem was in the pelvic area.
The shock on the faces of Cabinet ministers during Saturday's late-night broadcast signaled that uncertainty over the country's future reigns, even in the top echelons of power.
Chavez has been receiving treatment at Havana's Cimeq hospital as a guest of his close friend and political mentor, former Cuban leader Fidel Castro. He is guaranteed tight security and privacy on the communist-led Caribbean island.
The usually loquacious Venezuelan leader had sharply cut back his appearances since winning the October 7 election, saying the campaign and radiation therapy had left him exhausted.
Under the constitution, an election would have to be held within 30 days if Chavez were to leave office in the first four years of his next six-year term, due to begin on January 10. at would also be the case should he not be able to start the term.
For the first time, in a surprise admission he might not be able to govern for as long as he hopes, he singled out long- time ally Maduro as his candidate.
"He is a complete revolutionary, a man of great experience despite his youth, with great dedication and capacity for work," Chavez said. "In a scenario where they were obliged to hold a new presidential election, you should choose Nicolas Maduro."
Maduro's trade union background appeals to Chavez's working-class supporters, while his years as foreign minister provided opportunities for networking abroad.
He may win less support from the military wing of the Socialist Party, which controls many top government posts.
The naming of Maduro appeared to sideline Diosdado Cabello, a Congress head and former military comrade of Chavez with close ties to the armed forces. Chavez urged "unity" over-and-over again in his comments.
"I never argue with Chavez's instructions, I obey them," Cabello said shortly afterwards.
"I am at the service of the vice-president, at the service of the fatherland."
The opposition could find itself in its best position to oust his administration since Chavez took power in 1999. Many voters have ignored the failings of Chavez's government because of their intense emotional connection to him.
Any new election would potentially give just-defeated presidential candidate Henrique Capriles another chance.
Capriles lost to Chavez in October, but garnered 44 percent and a record 6.5 million votes for the opposition.
Though past polls have shown Capriles is more popular than any of Chavez's allies, including Maduro, the vice p resident will benefit from his boss's personal blessing.
Venezuela's widely traded bonds are likely to soar when markets open on Monday on expectations that Chavez's renewed illness will pave the way for a more market-friendly government. Its bonds have been among the most profitable of any emerging market paper this year, largely due to Chavez's weak health.
Chavez's cancer saga has once again distracted attention from major national issues like state elections in a week, a possible devaluation of the local bolivar currency, and a proposed amnesty for jailed and exiled political foes.