This comes after a three-year political battle over wider access.
Barr Pharmaceuticals Inc's Plan B must stay behind pharmacy counters, the Food and Drug Administration said on Thursday.
Women must show proof they are at least 18 to buy the emergency contraceptive pills without a prescription. Under-18s still need a doctor's order.
The FDA said in a statement that "when used as directed, Plan B effectively and safely prevents pregnancy".
Backers and opponents had lobbied the agency with arguments about Plan B's impact on abortion rates and teenage sex, and the feud stalled the nominations of two FDA commissioners.
Two Plan B pills can prevent pregnancy when taken within 72 hours of sexual intercourse.
Women's groups and other supporters argued that easier access would reduce the number of unwanted pregnancies and abortions.
Conservative opponents said wider availability would lead to more teenage promiscuity and sexually transmitted diseases.
Barr agreed to monitor enforcement of the age limit and to limit Plan B's distribution to health clinics and stores with pharmacies, the FDA said.
The pills should be available in non-prescription and prescription packages by the end of the year.
Prescription packages are already available.
The company originally had sought permission to sell Plan B over the counter without age limits.
Plan B pills contain higher doses of progestin, a hormone used in prescription birth-control pills.
The pills block the release or fertilisation of an egg.
Some research suggests that Plan B may also keep a fertilised egg from attaching to the womb, and some opponents considered that mechanism equal to an abortion.