The court ruled that the former employee of the facility deserved no leniency over the 2016 attack, which shocked the country.
"The lives of 19 people were taken away. This is profoundly grave," chief judge Kiyoshi Aonuma told the court.
Uematsu planned the murders and had "an extreme intention to kill", he added.
Prosecutors had sought the death penalty -- which in Japan is carried out by hanging -- and argued that the defendant was capable of taking responsibility for the violence at the Tsukui Yamayuri-en centre, just outside Tokyo.
Uematsu was impassive as the verdict was announced, looking straight ahead at the judge as he was sentenced.
He wore a black suit with his hair in a long ponytail down to his waist, and was flanked by six uniformed court officers wearing surgical masks.
Uematsu, who faced six charges including murder, reportedly said before the trial that he would not appeal any verdict, though he argued he did not deserve the death penalty.
He has reportedly said he wanted to eradicate all disabled people in the horrifying attack that also left 26 people wounded.
He turned himself in to police after the assault, carrying bloodied knives.
It later emerged he had left his job at the home just months earlier and been forcibly hospitalised after telling colleagues he intended to kill people at the centre.
But he was discharged after just 12 days when a doctor decided he was not a threat. He had also written a letter outlining plans to attack the home, claiming "disabled people only create unhappiness".
Among the few victims to be identified publicly was a 19-year-old woman, Miho, whose mother said Uematsu "didn't need a future".
"I hate you so much. I want to rip you apart. Even the most extreme penalty is light for you. I will never forgive you," the mother said before the verdict, according to public broadcaster NHK.
"Please bring back my most precious daughter... You're still alive. It's not fair. It's wrong."
"I demand capital punishment," she added.
Takashi Ono, whose son was severely injured in the attack, told reporters he was "relieved".
"The judge gave the sentence the victims' families hoped for," he said.
However, some questioned the need for the death sentence, a policy that faces little major opposition in Japan.
"It shouldn't have been the death sentence. We should have allowed him to learn better," said Rie Sumida, a disabled 45-year-old woman waiting for the verdict.
"If you kill the person because of what he did, it means you do the same thing as Uematsu," she told AFP.
The head of the care home, Kaoru Irikura, had tears in her eyes as she described listening to the verdict.
"When the judge explained Uematsu's motives again today, I imagined each scene" from the day of the attack, she said tearfully.
"I want him to have to face what he has done until the day he dies."
The trial was closely watched, and a court spokesman said more than 1,600 people lined up for 10 seats available for the verdict.
The number of spots was reduced because of rules requiring spectators to sit apart to prevent the spread of coronavirus.
Uematsu has shown no remorse for the attack, telling Japan's Mainichi Shimbun daily that people with mental disabilities "have no heart", and for them "there's no point in living".
Uematsu's beliefs shocked Japan, with experts and activists raising questions about whether others might hold similar views.
Japan has been making efforts to increase accessibility -- particularly in Tokyo ahead of this year's Paralympic Games -- and activists hailed last year's election of two disabled lawmakers.
But some critics feel the country still falls short of fully integrating people with disabilities.
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