On January 19, 2006, New Horizons was launched from Cape Canaveral Air Force Station by an Atlas V rocket directly into an Earth-and-solar escape trajectory with a speed of about 16.26 km/s (10.10 mi/s; 58,500 km/h; 36,400 mph).

On July 14, 2015, at 11:49 UTC, it flew 12,500 km (7,800 mi) above the surface of Pluto,[13][14] which at the time was 34 AU from the Sun,[15] making it the first spacecraft to explore the dwarf planet.

[20][21] In August 2018, NASA cited results by Alice on New Horizons to confirm the existence of a "hydrogen wall" at the outer edges of the Solar System.

Stamatios "Tom" Krimigis, head of the Applied Physics Laboratory's space division, one of many entrants in the New Frontiers Program competition, formed the New Horizons team with Alan Stern in December 2000.

New Horizons topped the list of projects considered the highest priority among the scientific community in the medium-size category; ahead of missions to the Moon, and even Jupiter.

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.

[55] As a point of departure, the team took inspiration from the Ulysses spacecraft,[56] which also carried a radioisotope thermoelectric generator (RTG) and dish on a box-in-box structure through the outer Solar System.

A 7075 aluminium alloy tube forms the main structural column, between the launch vehicle adapter ring at the "rear", and the 2.1 m (6 ft 11 in) radio dish antenna affixed to the "front" flat side.

While the spacecraft is cruising inactively in the cold outer Solar System, the louvers are closed, and the shunt regulator reroutes power to electric heaters.

The high-gain dish has a Cassegrain reflector layout, composite construction, of 2.1-meter (7 ft) diameter providing over 42 dBi of gain and a half-power beam width of about a degree.

The 208.3 mm (8.20 in) aperture Ritchey–Chretien mirrors and metering structure are made of silicon carbide to boost stiffness, reduce weight and prevent warping at low temperatures.

[74] The PEPSSI sensor has been designed to measure the mass, energy and distribution of charged particles around Pluto, and is also able to differentiate between protons, electrons, and other heavy ions.

[75] Alice is an ultraviolet imaging spectrometer that is one of two photographic instruments comprising New Horizons' Pluto Exploration Remote Sensing Investigation (PERSI); the other being the Ralph telescope.

The VBSDC is always turned on measuring the masses of the interplanetary and interstellar dust particles (in the range of nano- and picograms) as they collide with the PVDF panels mounted on the New Horizons spacecraft.

[84][85] The probe finally lifted off from Pad 41 at Cape Canaveral Air Force Station, Florida, directly south of Space Shuttle Launch Complex 39, at 19:00 UTC on January 19, 2006.

[96] During the week of February 20, 2006, controllers conducted initial in-flight tests of three onboard science instruments, the Alice ultraviolet imaging spectrometer, the PEPSSI plasma-sensor, and the LORRI long-range visible-spectrum camera.

Redundant components as well as guidance and control systems were shut down to extend their life cycle, decrease operation costs and free the Deep Space Network for other missions.

A study based on 18 months of computer simulations, Earth-based telescope observations and occultations of the Pluto system revealed that the possibility of a catastrophic collision with debris or dust was less than 0.3% on the probe's scheduled course.

Before activating the other two instruments, ground tests were conducted to make sure that the expanded data gathering in this phase of the mission would not limit available energy, memory and fuel in the future and that all systems were functioning during the flyby.

[136] Starting on May 11, a hazard search was performed, looking for unknown objects that could be a danger to the spacecraft, such as rings or hitherto undiscovered moons, which could then possibly be avoided by a course change.

[138] The object would be too distant to resolve surface features or take spectroscopy, but it would be able to make observations that cannot be made from Earth, namely a phase curve and a search for small moons.

[139] On July 4, 2015, New Horizons experienced a software anomaly and went into safe mode, preventing the spacecraft from performing scientific observations until engineers could resolve the problem.

[150] Soon after the Pluto flyby, in July 2015, New Horizons reported that the spacecraft was healthy, its flight path was within the margins, and science data of the Pluto–Charon system had been recorded.

[155] The transfer was completed on October 25, 2016, at 21:48 UTC, when the last piece of data—part of a Pluto–Charon observation sequence by the Ralph/LEISA imager—was received by the Johns Hopkins University Applied Physics Laboratory.

[citation needed] Mission planners searched for one or more additional Kuiper belt objects (KBOs) of the order of 50–100 km (30–60 mi) in diameter as targets for flybys similar to the spacecraft's Plutonian encounter.

By participating in a citizen-science project called Ice Hunters the public helped to scan telescopic images for possible suitable mission candidates.

[194] By December 2023, New Horizons had discovered a total of about 100 KBOs, and flown close enough to about 20 of them to capture characteristics such as shape, rotational period, possible moons, and surface composition.

In addition, since 2021, Canadian researchers had been able to use machine learning software to speed up identification processes of potential KBO targets for a third flyby, cutting weeks-long efforts to hours-long.

[194][195] Science objectives of the flyby included characterizing the geology and morphology of Arrokoth[196][197] and mapping the surface composition (by searching for ammonia, carbon monoxide, methane, and water ice).

[222] New Horizons may also take a picture of Earth from its distance in the Kuiper belt, but only after completing all planned KBO flybys and imaging Uranus and Neptune.