Mars Express will skim past the irregularly-shaped moon at a distance of just 45 kilometres.
The spacecraft will be so close and travelling so fast that it will not be able to capture any images of the moon's surface. Instead, it will yield valuable new data on the object's gravitational field and internal structure.
Scientists are still uncertain about the origin of Phobos, which resembles a lumpy rock just 27 kilometres wide, and its smaller sibling Deimos.
Leading theories are that the pair are either captured asteroids or the remnants of debris thrown up by giant impacts on Mars.
Observations during earlier fly-bys have suggested that between a quarter and a third of Phobos could be empty space. This suggests that the object may essentially be a rubble pile with large spaces between the rocky blocks making up its interior.
Mars Express will also be making measurements of how the solar wind - the stream of energetic particles emitted by the Sun - affects the moon.
"At just 45 km from the surface, our spacecraft is passing almost within touching distance of Phobos," said Mars Express operations manager Michel Denis.
"We've been carrying out manoeuvres every few months to put the spacecraft on track and, together with the ground stations that will be monitoring it on its close approach, we are ready to make some extremely accurate measurements at Phobos."
As the spacecraft passes close to Phobos, it will be pulled slightly off course by the tug of the moon's gravity, altering its velocity by a few centimetres per second.
The tiny deviations will be reflected in the space craft's radio signals as they are beamed back to Earth. Scientists can then translate them into measurements of the mass and density structure inside the moon.
Although no pictures will be taken during the actual fly-by, the high resolution stereo camera carried by Mars Express has been capturing images for weeks as it approached closer to the moon.