On its website, the National Federation of Independent Business states that it is a "nonprofit, nonpartisan organization founded in 1943". In 2010, 25 of its members, all Republican, were elected to the 112th Congress.

Since 1990, it has donated $725,551 to Democratic candidates and party committees versus $11,972,074 to Republican candidates or party committees. It was a key opponent of President Bill Clinton's attempt to reform American health care in 1993.

In 2010, the NFIB became the lead plaintiff opposing the Patient Protection and Affordable Care Act health care reform legislation. The organization joined 26 states in the lawsuit challenging the constitutionality of the act. The case reached the Supreme Court, which issued its ruling on National Federation of Independent Business v. Sebelius on June 28, 2012, upholding most provisions of the act. Karl Rove's conservative Crossroads GPS PAC gave NFIB $3.7 million to help fund the court fight.