New Horizons is about the size of a baby grand piano and has been described as the fastest spaceship ever built. It is currently moving at a speed of 49,570 kilometers per hour.
NASA is gearing to receive the information from the far-flung space explorer that will reveal specifics of Pluto previously only subject to speculation.
The closest approach is set for 7:49 AM (1719 IST). NASA television coverage begins at 7:30 AM.
But it will be hours before scientists hear back from the spacecraft - the first to visit an unexplored planet since the NASA Voyager missions launched in the 1970s - because New Horizons will be busy snapping pictures and collecting data.
It is supposed to send a "phone home" signal to Earth at 4:20 PM, but that will take nearly five hours to reach scientists.
So NASA will not announce until about 13 hours after the flyby, at 9:02 PM (0632 IST tomorrow), whether or not the spacecraft survives the high-speed encounter.
According to principal investigator Alan Stern, there is a one in 10,000 chance that the spacecraft could be lost in a collision with debris around Pluto, long considered the farthest planet from the Sun until it was reclassified as a "dwarf planet" in 2006.
"Until we pass that point... We won't really know with certainty that we cleared the system and that there were no debris strikes," Stern said.
Stern said experts have searched for potential debris and not found any of concern.
Never before has a spacecraft ventured into the Kuiper Belt, and New Horizons has been on its way there for more than nine years - a journey of some three billion miles.
It will pass by Pluto at a distance of 12,500 kilometers.
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