Pluto is the largest object in the Kuiper Belt, the vast swarm of hundreds of thousands of objects orbiting the Sun beyond Neptune. Many of these objects have been undisturbed and unaltered since the beginning of the solar system, and thus harbor many secrets about the formation of the planets. After the Pluto flyby, New Horizons headed deeper into the Kuiper Belt, providing an opportunity to explore other, smaller and more primitive Kuiper Belt objects (KBOs). An extensive search with ground-based telescopes and the Hubble Space Telescope resulted in the discovery, in summer 2014, of two KBOs that were close enough to the spacecraft's trajectory that the spacecraft could be diverted to perform a close flyby of one of them.

Shortly after the Pluto flyby, in August 2015, the team chose one of these, 2014 MU69 (now nicknamed Ultima Thule) as the flyby target. In early November 2015 New Horizons fired its thrusters to alter the direction of its trajectory by 1/4 of a degree, to set a course toward a close flyby of Ultima on January 1, 2019.

The spacecraft's path to Ultima takes it through the densest part of the Kuiper Belt, passing within 1 astronomical unit (the distance between Earth and the Sun, which is about 150 million kilometers or 93 million miles) of about a dozen other known KBOs. Though none of these will appear as more than a point of light in New Horizons' cameras, the spacecraft will observe them from unique angles not possible from Earth to learn about their surface properties, and will search for moons and rings with greater sensitivity than the most powerful telescopes on or near Earth. New Horizons is also taking pictures of several larger but more distant Kuiper Belt objects, including several dwarf planets, to measure their brightness from its unique perspective.

The approach to Ultima began in August 2018, when the spacecraft took its first pictures of its target, which appeared as a faint dot barely visible against a crowded field of stars. The spacecraft continues to take regular images of Ultima as it gets closer and brighter, using them to check that it is on the right course, and firing its thrusters to make course corrections as necessary. In early December, the spacecraft performs an intensive campaign of imaging to look for any rings or moons around Ultima. If danger is found along the planned trajectory, designed for a closest approach distance of 3,500 km (2,175 miles), the team can divert to a more distant alternate trajectory (close approach distance of 10,000 km or 6,214 miles) as late as December 18, 16 days before the flyby.

In the last few days of the approach, the navigation team will analyze the latest images of Ultima taken by New Horizons to refine estimates of the KBO's position relative to the spacecraft. If necessary the team will uplink the updated information to New Horizons, so that the spacecraft can more accurately time its observations and point its cameras.

Intensive science observations begin 24 hours before the flyby. The spacecraft will take frequent grayscale, color, near-infrared and ultraviolet observations of Ultima as it rotates, to investigate its shape, composition, and any possible gas releases, on all sides of the object. Long-exposure imaging of the space surrounding Ultima will search for rings or moons and determine their orbits. The closest approach observations, taken during the hour or so nearest closest approach, need to account for that Ultima's position is uncertain – that's why these observations consist of long scans to obtain color and grayscale images, and infrared spectra, of all the possible places where Ultima might be. The pixel sizes of the best expected color and grayscale images and infrared spectra will be 330 meters, 140 meters, and 1.8 kilometers, respectively. There is a chance of higher resolution grayscale images, with 33-meter pixels, if the high-resolution Long Range Reconnaissance Imager (LORRI) is able to point accurately at Ultima –but the necessary accuracy isn't guaranteed. The team will also attempt to detect the daytime and nighttime heat radiation from Ultima using the radio instrument.

After closest approach – set for 12:33 a.m. EST on January 1, 2019 – New Horizons will point its ultraviolet instrument at the Sun to look for absorption of ultraviolet light by any gases being released by Ultima (though detection of such outgassing is unlikely). It will also make additional searches for rings around Ultima. Four hours after the flyby, the spacecraft will turn briefly to Earth to report that the flyby was successful. A few hours after that, it will begin the roughly two-year process of downlinking the approximately seven gigabytes of data acquired during the flyby.