A criminal complaint against former traders Tom Hayes and Roger Darin was unsealed in a district court in New York, the US Justice Department said.
Both traders were charged with conspiracy, while Hayes was also charged with wire fraud and an antitrust offence.
Announcing the charges, US Attorney General Eric Holder said: "By causing UBS and other financial institutions to spread false and misleading information about Libor, these alleged conspirators - and others at UBS - manipulated the benchmark interest rate upon which many consumer financial products -including credit cards, student loans, and mortgages - are frequently based.
"They defrauded the company's counterparties of millions of dollars. And they did so primarily to reap increased profits, and secure bigger bonuses, for themselves."
Another official said the US would seek the extradition of the pair, one of whom is believed to be in England. The other former employee is said to be in Switzerland.
The Justice Department official said: "We're going to seek their extradition and our investigation continues.
" ... Mr Hayes obviously was a very, very major trader, and we're going to continue to move forward."
The charges came as the Swiss bank agreed to pay a £940m ($1.5bn) fine to US, UK and Swiss authorities to resolve related allegations. It is the second-biggest fine ever imposed on a bank.
The penalty was for "widespread and routine" attempts to manipulate key inter-bank lending rates, including Libor.
UBS has also admitted market abuse in the US, Japan and Switzerland.
The FSA said at least 45 of the bank's staff were involved, with traders, managers and senior managers colluding to fix rates both to make money and, during the financial crisis, to make the bank appear stronger than it was.
Meanwhile, a new financial services law has been approved in the UK to make the rigging of Libor and other market benchmarks a criminal offence from next April - with tougher penalties.
But the law will not be applied in retrospect, meaning the FSA will have to continue fining on the basis of breaches of general conduct principles.
The Libor rate is a reference point for vast ranges of financial contracts around the world worth about £184 trillion.
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