The rates affect the costs of hundreds of trillions of dollars in loans and investments such as bonds, auto loans and derivatives.
The U.S. Commodity Futures Trading Commission said Wednesday that the incidents occurred between 2005 and 2009 and sometimes took place daily.
The CFTC said Barclays senior management and multiple traders were involved in the matter and that they also co-ordinated with traders at other banks to make false submissions.
"Banks must not attempt to influence LIBOR or other indices based upon concerns about their reputation or the profitability of their trading positions," CFTC Chairman Gary Gensler said in a statement.
The data was used in determining the London interbank offered rate — known as LIBOR— and Euribor rates, which influence many other interest rates.
The LIBOR is an average rate set by banks each morning that measures how much they're going to charge each other for loans.
Barclays' settlement with the CFTC includes a $200 million civil penalty. Britain's Financial Services authority levied a fine of 59.5 million pounds ($92.7 million), the biggest fine ever imposed by the British regulator. Barclays also agreed to pay $160 million as part of an agreement with the fraud section of the Justice Department's criminal unit on a related matter.
Barclays President Bob Diamond also announced he and three senior bank executives were waiving any bonus for the year as a result of the case.
The other executives include Group Finance Director Chris Lucas, Chief Operating Officer Jerry del Missier and Chief Executive of Corporate and Investment Banking Rich Ricci.