Settlement of the civil and criminal mis-selling claims is expected to be finalized in 2012. It includes a Department of Justice investigation into the company's controversial diabetes drug Avandia, which has been linked to heart risks.
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Britain's biggest drugmaker already took massive charges last year related to liability claims from patients who had been taking Avandia.
The company's current legal provisions stand at 2.9 billion pounds ($4.6 billion).
The deal to resolve the latest disputes follows a clampdown in the United States on unfair pharmaceutical industry practices that has forced major drugmakers to rethink the way they do business in the world's biggest market.
Since 2000 the number of industry settlements with U.S. states and the federal government has soared as authorities have taken an increasingly tough line on practices that may have put commercial goals above the interests of payers and patients, such as marketing drugs for unapproved uses.
Announcing the outline settlement on Thursday, GSK said it had implemented fundamental changes to U.S. selling procedures in recent years and Chief Executive Andrew Witty said the cases "do not reflect the company that we are today."
Changes under Witty's watch include a new bonus system for U.S. sales representatives, who no longer work to individual sales targets. Witty has also overhauled the group's top U.S. management.
Despite the hefty settlement cost -- equal to about 2.8 percent of GSK's market value -- the shares were up 0.7 percent at 1230 GMT, in line with the Stoxx Europe 600 healthcare sector index, as investors accepted the need to clear the decks of long-running legal claims.
Analysts at Helvea said the deal was positive news as it would reduce financial uncertainty for the group.
Since the settlement of $3 billion is covered by existing legal provisions, there is no need to raise new money and GSK said payments would be funded through existing cash resources.
The disputes being settled include an investigation that started in Colorado and moved to Massachusetts, related to improper marketing of drugs between 1997 and 2004.
Another probe involves charges that GSK used the Medicaid system improperly to make additional profit from sales to the federal program, while the Avandia case covers investigations into the way the drug was developed and then marketed.
In mid-2010, GSK took a $2.4 billion charge after settling most patient liability claims relating to Avandia, as well as an investigation into its former factory at Cidra in Puerto Rico, and anti-trust and product liability litigation over antidepressant Paxil.
Several other leading drugmakers have also struck big-ticket settlement deals in United States in recent years, or have been forced to take big charges in anticipation of such deals.
Only last month, Abbott Laboratories took a $1.4 billion charge related to attempts to settle a U.S. federal investigation into marketing of its Depakote anticonvulsant drug.
In 2009, Pfizer paid $2.3 billion for pitching its now-withdrawn Bextra arthritis drug and another dozen medicines to patients and doctors for unapproved uses. Eli Lilly paid $1.4 billion the same year after being accused of improperly marketing its antipsychotic drug Zyprexa for use in children and elderly patients.
($1=0.626 British pounds)
(Editing by Greg Mahlich)