The award was the latest in a series of court defeats for Monsanto over Roundup. The company insists the glyphosate-based product is not linked to cancer.
The couple's legal team described the damages award as "historic," saying it totaled $2.055 billion after adding in slightly more than $55 million in compensatory damages.
"The jury saw for themselves internal company documents demonstrating that, from day one, Monsanto has never had any interest in finding out whether Roundup is safe," said plaintiff's counsel Brent Wisner.
"Instead of investing in sound science, they invested millions in attacking science that threatened their business agenda."
In a statement, Bayer said it was disappointed with the jury's decision and would appeal the verdict, which it argues was at odds with a recent US Environmental Protection Agency review of glyphosate-based weed killers.
"The consensus among leading health regulators worldwide is that glyphosate-based products can be used safely and that glyphosate is not carcinogenic," Bayer said.
The verdict in a California state court in Oakland was the third courtroom defeat for Bayer in cases accusing the chemicals in Roundup of causing cancer.
Glyphosate developer Monsanto was convicted in the United States in 2018 and 2019 of not taking necessary steps to warn of the potential risks of Roundup -- their weedkiller containing the chemical, which two California juries found caused cancer in two users.
"Unlike the first two Monsanto trials, where the judges severely limited the amount of plaintiffs' evidence, we were finally allowed to show a jury the mountain of evidence showing Monsanto's manipulation of science, the media and regulatory agencies to forward their own agenda despite Roundup's severe harm to the animal kingdom and humankind," said attorney Michael Miller, who was co-lead trial counsel along with Wisner.
Bayer announced last month that over 13,000 lawsuits related to the weedkiller had been launched in the US.
The stunning verdict came the same day that German chemical giant Bayer admitted that its subsidiary Monsanto could have kept lists of key figures -- for or against pesticides -- in European countries.
Bayer apologized Sunday after it emerged that Monsanto had a PR agency collate lists of French politicians, scientists and journalists, with their views on pesticides and GM crops.
"I think it's very likely that such lists also exist in other European countries," Matthias Berninger, Bayer's head of Public Affairs, told journalists in a conference call.
Berninger said he "firmly believes that other countries in Europe will be affected.
"We consider what we have seen so far to be completely inappropriate," he said.
"However, we were of the opinion that the reports of these dealings with journalists, politicians and activists are not in order and not in agreement with what Bayer stands for."
The German agro-chemicals and drugs giant finalized the acquisition of the US company Monsanto last year for $63 billion.
But the deal has turned out to be plagued with other massive costs.
Just two months after the acquisition was completed, Monsanto lost a case to a school groundskeeper suffering from terminal non-Hodgkin's lymphoma. He had sued the company over the glyphosate weedkillers Roundup and Ranger Pro.
Monsanto was initially ordered to pay $289 million to Johnson, before the damages were reduced to $78.5 million.
In March, the company lost another case to an American retiree who blames his cancer on the weedkiller, and was ordered by a court to pay $80 million to the plaintiff.
French authorities have opened a preliminary enquiry into claims Monsanto had information illegally collected on the views and pliability of hundreds of high-profile figures and media outlets.
Monsanto allegedly had public relations agency FleishmanHillard draw up files on their opinions on the controversial weedkiller glyphosate and on genetically modified crops.