This depends on how you break down the categories of federal government spending. If you break the spending down into specific programs, you get one answer. If you just break it down into broad categories, you get another.
The most usual answer is that the number one expenditure for the federal government is what is called "income security" or "transfer payments." These are payments made to individuals where the people who get the money do not have to do anything (at least not in the current time period) in exchange for the money. This includes welfare payments, but the biggest portions of this part of the budget go to things like Social Security and Medicare.
This type of payment makes up somewhere around 40% of the federal budget. This is why it is so hard to cut government spending. The Republicans who have taken over the House of Representatives want to cut spending, but have said they will not touch Medicare or Social Security. Since these are a huge chunk of the budget, they will have a hard time.
By most ways of breaking down the budget, the next largest category is spending on national defense, which is about 20% of the budget.