The comet, known as Siding Spring (C/2013 A1), is set to hurtle past Mars at a distance of about 140,000km.
The closest pass is expected to happen on Monday at 5am (AEDT).
Astronomers do not expect it to collide with Mars, but hope it will pass close enough to reveal clues about the origins of the solar system.
The comet is believed to have originated billions of years ago in the Oort Cloud, a distant region of space on the outskirts of the solar system.
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"Comets such as C/2013 A1 are essentially dirty, icy snowballs with rocks and dust embedded in frozen gases," Nottingham Trent University astronomy expert Dan Brown.
The comet is believed to have originated billions of years ago in the Oort Cloud, a distant region of space on the outskirts of the solar system.
"It is on its first run towards the centre of our solar system, and its material is virtually unchanged by the rays of the sun and can give us an insight into the material composition of our early solar system 4.6 billion years ago."
The comet, about 1.6 km in diameter, is travelling at nearly 200,000 km per hour and is only about as solid as a pile of talcum powder.
The comet has travelled for more than one million years to make its first pass by Mars, and will not return for another million years, after it completes its next long loop around the sun.
NASA has manoeuvred its Mars orbiters to the far side of the planet so they won't be damaged by any high-speed comet debris.
But scientists hope the Mars Reconnaissance Orbiter, Mars Odyssey and MAVEN will capture a data about the fly-by.
NASA's two rovers, Curiosity and Opportunity, will send back pictures of the comet's pass, the US space agency said.
"The orbiters will keep a close eye on the show," said Rebecca Johnson, editor of StarDate magazine.
"They'll study the comet itself, which is a small chunk of ice and rock. They'll also study the cloud of gas and dust around the comet, as well as its long tail.
"And they'll measure how the gas and dust interact with the Martian atmosphere."
The comet has travelled for more than one million years to make its first pass by Mars, and will not return for another million years, after it completes its next long loop around the sun.
The comet was discovered by Robert McNaught at Australia's Siding Spring Observatory in January 2013.
Its fly-by of Mars is not likely to be visible to sky watchers on Earth.
"As it zips toward the sun, it gives scientists a chance to see a relic from the distant past - a snowball that preserves the same ingredients that gave birth to our own world," said Johnson.
