"Brother Number Two" Nuon Chea, 88, and former head of state Khieu Samphan, 83, were "guilty of the crimes against humanity, of extermination... political persecution, and other inhumane acts," said judge Nil Nonn.
The pair are entitled to appeal the verdict, but the judge said the gravity of the crimes meant they "shall remain in detention until this judgment becomes final".
Laywers for the pair said they would appeal the verdicts and life jail terms.
"We will appeal the verdict and sentence... it is unjust for my client. He did not know or commit many of these crimes," Son Arun, a lawyer for Nuon Chea, 88, told reporters.
Kong Sam Onn, a lawyer for the second defendant, 83-year-old former regime head of state Khieu Samphan, said: "This is not justice... We will appeal the verdict and sentence."
Prosecutors had sought life terms for the defendants -- the most senior surviving ex-Khmer Rouge officials -- for their roles in a regime which left up to two million people dead during the "Killing Fields" era from 1975-1979.
The verdict, after a two-year trial, is likely to bring a measure of justice to those who survived the Khmer Rouge years, three decades after the regime's fall.
The era saw a quarter of Cambodia's population killed or die from starvation and overwork.
A few dozen survivors, many travelling from far-flung rural provinces, arrived early to join some 900 Cambodians at the Phnom Penh-based court to watch the verdicts.
The defendants had throughout the trial denied knowledge of the regime's crimes during the era.
But both eventually expressed a level of remorse for the suffering inflicted on the Cambodian people by the Khmer Rouge.
The complex case against them was split into a series of smaller trials in 2011 for reasons including their advanced age and the large number of accusations.
Led by "Brother Number One" Pol Pot, who died in 1998, the Khmer Rouge dismantled modern society with regime atrocities affecting virtually every family in Cambodia.
Soum Rithy (C), a Cambodian survivor of the Khmer Rouge, cries as he hugs Chum Mey (R), a prominent survivor of Tuol Sleng prison (S-21), after hearing the verdict (AAP)
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