The white Atlas rocket, named Maven (Mars Atmosphere and Volatile Evolution), blasted off on schedule at 6.28pm from Cape Canaveral Air Force Station in Florida.
The lift-off of the £417 million craft, followed a successful separation from the rocket 52 minutes later, kicking off the 10-month journey to the Red Planet.
Omar Baez, Nasa's flight director, described the lift-off and separation as "flawless."
Arrival at Mars is scheduled for September 2014, with the science mission of the solar-wing panelled orbiter set to begin two months later.
The probe is different from past NASA missions because it focuses not on the dry surface but on the mysteries of the never-before-studied upper atmosphere.
Much of MAVEN's year-long mission will be spent circling the planet 3,800 miles above the surface.
However, it will execute five deep dips to a distance of just 78 miles above the Martian landscape to get readings of the atmosphere at various levels.
Researchers have described the mission as a search for a missing piece to the puzzle of what happened to Mars' atmosphere, perhaps billions of years ago, to transform Earth's neighbour from a water-bearing planet that might have been favourable for life to a dry, barren desert.
"Maven is the first spacecraft devoted to exploring and understanding the Martian upper atmosphere," the US space agency said.
"The spacecraft will investigate how the loss of Mars' atmosphere to space determined the history of water on the surface."
One of its three scientific tools is a solar wind and ionosphere gauge called the Particles and Fields Package, built by the University of California at Berkeley Space Sciences Laboratory.
A second tool, called the Remote Sensing Package, was built by the Laboratory for Atmospheric and Space Physics at the University of Colorado and will determine global characteristics of the upper atmosphere and ionosphere.
The third instrument, the Neutral Gas and Ion Mass Spectrometer, was built by Nasa's Goddard Space Flight Center.
It will measure the composition and isotopes of neutrals and ions.
"With Maven, we're exploring the single biggest unexplored piece of Mars so far," said the mission's principal investigator, Bruce Jakosky.
Nasa has sent a series of rovers to explore the surface of the Red Planet, including its latest, Curiosity, which arrived last year.
The deep space orbiter launched earlier this month by India seeks to find traces of methane from Mars and is on track to arrive two days later than the US spacecraft.
The science goals of the two do not overlap much.
The Indian probe will be searching for methane which could prove the existence of some ancient life form, while the US probe seeks answers about the planet's climate change.
Nasa scientists have said they look forward to sharing data between the two missions.
Maven's findings are expected to help pave the way for a future visit by humans to the Red Planet, perhaps as early as 2030, Nasa has said.