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After separation from the launch vehicle, overall control was taken by Mission Operations Center at the Applied Physics Laboratory in Howard County, Maryland. The science instruments are operated at Clyde Tombaugh Science Operations Center in Boulder, Colorado. Navigation is performed at various contractor facilities, whereas the navigational positional data and related celestial reference frames are provided by the Naval Observatory Flagstaff Station through Headquarters NASA and JPL; KinetX is the lead on the New Horizons navigation team and is responsible for planning trajectory adjustments as the spacecraft speeds toward the outer Solar System. Coincidentally the Naval Observatory Flagstaff Station was where the photographic plates were taken for the discovery of Pluto's moon Charon; and the Naval Observatory is itself not far from the Lowell Observatory where Pluto was discovered. New Horizons was originally planned as a voyage to the only unexplored planet in the Solar System. When the spacecraft was launched, Pluto was still classified as a planet, later to be reclassified as a dwarf planet by the International Astronomical Union. Some members of the New Horizons team, including Alan Stern, disagree with the IAU definition and still describe Pluto as the ninth planet. Pluto's satellites Nix and Hydra also have a connection with the spacecraft: the first letters of their names are the initials of New Horizons. The moons' discoverers chose these names for this reason, plus Nix and Hydra's relationship to the mythological Pluto. In addition to the science equipment, there are several cultural artifacts traveling with the spacecraft. These include a collection of 434,738 names stored on a compact disc, a piece of Scaled Composites's SpaceShipOne, a "Not Yet Explored" USPS stamp, and a Flag of the United States, along with other mementos. About 30 grams (1 oz) of Clyde Tombaugh's ashes are aboard the spacecraft, to commemorate his discovery of Pluto in 1930. A Florida-state quarter coin, whose design commemorates human exploration, is included, officially as a trim weight. One of the science packages (a dust counter) is named after Venetia Burney, who, as a child, suggested the name "Pluto" after its discovery.

Mariner 10 was the first spacecraft to make use of an interplanetary gravitational slingshot maneuver, using Venus to bend its flight path and bring its perihelion down to the level of Mercury's orbit. This maneuver, inspired by the orbital mechanics calculations of the Italian scientist Giuseppe Colombo, put the spacecraft into an orbit that repeatedly brought it back to Mercury. Mariner 10 used the solar radiation pressure on its solar panels and its high-gain antenna as a means of attitude control during flight, the first spacecraft to use active solar pressure control. The components on Mariner 10 can be categorized into four groups based on their common function. The solar panels, power subsystem, attitude control subsystem, and the computer kept the spacecraft operating properly during the flight. The navigational system, including the hydrazine rocket, would keep Mariner 10 on track to Venus and Mercury. Several scientific instruments would collect data at the two planets. Finally, the antennas would transmit this data to the Deep Space Network back on Earth, as well as receive commands from Mission Control. Mariner 10's various components and scientific instruments were attached to a central hub, which was roughly the shape of an octagonal prism. The hub stored the spacecraft's internal electronics. The Mariner 10 spacecraft was manufactured by Boeing. NASA set a strict limit of US$98 million for Mariner 10's total cost, which marked the first time the agency subjected a mission to an inflexible budget constraint. No overruns would be tolerated, so mission planners carefully considered cost efficiency when designing the spacecraft's instruments. Cost control was primarily accomplished by executing contract work closer to the launch date than was recommended by normal mission schedules, as reducing the length of available work time increased cost efficiency. Despite the rushed schedule, very few deadlines were missed. The mission ended up about US$1 million under budget.

Die Explorer-Serie erhielt damit die Chance, die ersten Satelliten in die Erdumlaufbahn zu heben, und war gegenüber dem Vanguard-Projekt überaus erfolgreich.