On board the high-tech jet, which departed from Houston at 11 a.m. local time on Monday: Boeing Chief Executive W. James McNerney Jr. and Jeff Smisek, chief executive of United Continental Holdings Inc.
The voyage, dubbed United Flight 1, holds deep symbolic weight for Boeing and United, which is the only American carrier to fly the 787.
The Dreamliner is emerging from months of tinkering and testing after the U.S. Federal Aviation Administration on Jan. 16 ordered all of the planes parked due to concerns about its lithium-ion battery system.
Boeing has redesigned elements of the plane after incidents of overheating, including a fire. Analysts predict that the three-month grounding has cost the company millions of dollars.
Last month, the aviation agency gave the OK for the Dreamliner to return to service. Already, the jet is flying via carriers such as Qatar Airways, Air India and Ethiopian Airlines Enterprise.
Several more companies -- including LOT Polish Airlines, Japan Airlines, ANA and Latam Airlines Group -- have said their planes will soon return to the skies.
Last month, Boeing said it is boosting the production rate of the airliner -- planning to make 10 each month by the end of the year, up from the current seven-a-month pace.
Before the planes were grounded in January, the company had delivered 50 Dreamliners to eight airlines globally.