Morales, 56, now serving his third term, was trying to change the constitution so he could run for re-election in 2019, potentially allowing the former coca grower to remain president until 2025.
With 3.6 per cent of votes counted, the 'no' camp was on 67 per cent, versus 33 per cent for 'yes', according to early official results from the electoral commission.
Full results are expected later on Monday.
Exit polls also showed he may have lost the vote, although by a narrower margin. An Ipsos poll had the "no" side at 52.3 per cent and "yes" at 47.7 per cent, while a Mori poll gave a 51 per cent to 49 per cent lead to the "no."
Bolivians prepare to cast their vote in El Alto, Bolivia Source: AAP
Speaking outside the presidential palace, Vice President Alvaro Garcia Linera insisted on Sunday evening that it was "clearly a dead heat" and the result could still be reversed.
"It could be that the tears of joy on some opposition politicians will turn into tears of dismay by the morning," he said.
If the result is confirmed as a loss for Morales, it would be another blow for South American's once dominant populist leftist movement that has suffered a series of recent electoral defeats across the continent.
Morales, Bolivia's first indigenous president, has been credited with slashing poverty in one of the region's poorest countries by spending a natural gas windfall on welfare programs and new infrastructure since taking office in 2006. He was re-elected in 2014 with 61 percent of the vote.
But a growing body of critics charge Morales' administration with corruption, waste and authoritarianism. Recent allegations about an ex-girlfriend whose company won lucrative government contracts have weighed heavily on his popularity.
In a middle-class neighborhood in a southern district of La Paz, 37-year-old Susana Macias said she had voted "no" as a form of rebellion.
"We feel we have been tricked. The people who are leading us are not who we thought they were," she said.
Even if he loses the referendum, Morales has plenty of time before the next election to pick a successor and otherwise influence Bolivia's future, said Michael Shifter, head of the Washington-based Inter-American Dialogue think tank.
"He is one of the most charismatic and powerful leaders in Bolivian history. It is unlikely he is going to just retire from politics," he said.
"But perhaps for the first time in a decade, it is possible to imagine a Bolivia without Evo that does not return to the old times of economic and racial exclusion," Shifter said.
The BBC reported that one exit poll suggests 52.3 per cent voted against the proposal to amend the constitution, while another suggests it was 51 per cent.
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