After an extensive uncrewed test campaign, NS-16 carried New Shepard's first four people in July 2021: Jeff Bezos, Mark Bezos, Wally Funk, and Oliver Daemen. The flight demonstrated the system's autonomous crew operations, rapid ascent, capsule separation, and independent booster and capsule recovery.

Later missions expanded from four to six seats and broadened the manifest across aviation, science, education, entertainment, engineering, exploration, philanthropy, and business. Several participants returned for a second flight, while research astronauts used the short microgravity interval for human-tended experiments.

By NS-38 in January 2026, Blue Origin reported 98 human seats and 92 individuals flown. The sequence forms a distinct operational archive: short missions, but a high cadence of different crews using the same reusable suborbital architecture.