The wide margin means Morales, a coca farmer who has said he will end a U.S.-backed anti-drug campaign aimed at eradicating the crop, will likely be declared president in January.
Morales had 45 percent of the vote and former President Jorge Quiroga had 33 percent in an Equipso Mori poll. A second poll by the private Ipsos Captura organization showed Morales with a slightly narrower lead of 44.5 percent to 34 percent for Quiroga. Minor candidates were getting the rest.
With six other candidates in the race and the nation bitterly divided over economic policies, neither man was likely to win a majority of the vote. That would give Bolivia's newly elected legislature the right to decide between the top two finishers in mid-January.
Bolivia is the world's third-largest grower of coca leaf, which has traditional, legal uses among the country's Indians but also is the raw material for making the cocaine that flows out of South America to feed the habits of drug users in the United States and elsewhere.
"If (the U.S.) wants relations, welcome. But `no' to a relationship of submission," Morales said after casting his ballot, talking with journalists where piles of coca leaves were spread atop a Bolivian flag.
The Aymara Indian street activist also referred to his status as a symbol for many of Bolivia's long-downtrodden Indians, who are a majority in this country of 8.5 million people.
"I am the candidate of those despised in Bolivian history, the candidate of the most disdained, discriminated against," he said after working through a crowd of admirers, some of whom rushed forward to kiss him before voting at a decrepit basketball court in the village school.
He compared the struggle of his Movement Toward Socialism party to those of Indian leaders who fought Spanish conquerers as well as to independence hero Simon Bolivar and socialist icon Che Guevara. But he also stressed the need to make changes peacefully.
"In this millennium, it's not a matter of raising arms to defeat capitalism, so inhumane and savage," he said. Rather, he said, he would "work democratically to change things, based on elections and on the conscience of the people."
Quiroga, meanwhile, urged voters not to accept vague promises by his rival.
"Don't be fooled," Quiroga, 45, said as he closed his campaign Thursday in the wealthy city of Santa Cruz, his base. "With your support we are going to show that the future of Bolivia is good and prosperous."
Quiroga served as president in 2001-02 after then-President Hugo Banzer became ill. He campaigned on a promise to sell Bolivia's vast natural gas reserves at higher prices and to improve education, health care and roads, power and other infrastructure.
Some Bolivians argue that the gas fields should be taken over by the state.
Voting was held under heavy police guard across the country. Hundreds of international monitors, including a group from the Organization of American States, made it one of the mostly closely watched elections in Bolivia's history.
The election also was deciding the vice president, all 27 Senate seats, 130 House seats and all nine governorships.
Morales draws much of his support from Indians, many of whom feel free-market policies of the past two decades have enriched the white elite at the expense of the poor majority. Extreme poverty afflicts about half the population and the unemployment rate is above 9 percent.
A victory for Morales would give Bolivia a president sure to be at odds with Washington. He counts Cuba's Fidel Castro and Venezuela's Hugo Chavez among his friends, along with leftists in Brazil, Argentina and Uruguay who have won power at the ballot box this decade.
"If he governs by really carrying out his agenda, which is quite a radical agenda, I think it's going to be very difficult for him," said Michael Shifter, a Latin American analyst at Inter-American Dialogue in Washington.
"He has to figure out how to satisfy the demands of his radical base who want a greater share of the national wealth and at the same time he's got to make sure the country's economically viable."
The winner will take office Jan. 22, succeeding caretaker President Eduardo Rodriguez, a Supreme Court justice appointed by Congress on June 8, two days after street protests ended the 18-month administration of Carlos Mesa.