"The future demands that we operate in a different way than we have in the past. So, let there be no doubt: this piece of legislation must mark an end to the old way of doing business, and the beginning of a new era of responsibility and accountability that the American people have every right to expect and demand."
Republican legislators - the minority in congress - had objected to the large spending commitment in light of soaring national debt.
"In just 50 days, congress has voted to spend about $1.2 trillion," Mitch McConnell, the Republican senate leader, said. "To put that in perspective, that's about $24bn a day, or about $1bn an hour - most of it borrowed."
The newly signed bill includes funds for the departments of transportation and agriculture, as well as measures that begin to roll back strict limits on travel and trade with Cuba.
Under the current law, US citizens can visit their family in Cuba once every three years. The new bill would change that to once a year.
Senators sent the bill to the White House on Tuesday following a contentious fight.
Many Republicans fought the bill because it raised government spending by eight per cent above fiscal 2008 levels, saying that it added more money to programmes already funded by the $787bn economic stimulus package approved last month.
Debate over the bill, which has at times been full of partisan rhetoric, may foreshadow even bigger battles over Obama's $3.55 trillion budget for 2010, and his plans to overhaul national health care, which congress will turn to in the coming weeks.