After two days of delays due to poor weather and a power outage, the 60m rocket, built by Lockheed Martin, lifted off on Thursday at 2pm EST (1900 GMT) from Cape Canaveral Air Force Station.
High winds at the Florida launch site forced the first scrub of the launch of the New Horizons spacecraft on Tuesday, followed on Wednesday by a storm-triggered power outage at the mission control center in Laurel, Maryland.
With an unprecedented five solid-fuel strap-on boosters, the rocket sent the relatively tiny spacecraft into space faster than any object launched by man before. It sprinted into the sky and quickly disappeared over the Atlantic Ocean.
Shortly after the liftoff, Bruce Buckingham, launch commentator, said: "The five solid rocket boosters are burning just fine, sending the New Horizons spacecraft on its way to the very edge of our solar system."
While not much is known about Pluto, by the time the probe arrives, scientists may have a better idea of what to look for.
The spacecraft is about the size and shape of a concert piano attached to a satellite dish.
It will study Pluto as well as the frozen, sunless reaches of the solar system known as the Kuiper Belt.
The Atlas 5 rocket began its nine
and a half year journey into space
Scientists believe that studying the region's icy, rocky objects can shed light on how the planets formed.
The launch has drawn attention from opponents of nuclear power because the spacecraft is powered by 10.8kg of plutonium, whose natural radioactive decay will generate electricity for the probe's instruments.
Nasa and the Department of Energy estimated the probability of a launch accident that could release plutonium at 1 in 350.
As a precaution, the agencies brought in 16 mobile field teams that can detect radiation, plus air samplers and monitors.