O'Brien received her Bachelor of Arts in Economics and Executive MBA in Finance from New York University Stern School of Business.

[8][9] Having trekked to Mount Everest base camp and reached the summits of a number of notable mountains, including five of the world's fourteen 8,000-meter peaks (Shishapangma, Everest, Cho Oyu, Manaslu, and K2), including summiting two eight thousanders back-to-back just 8 days apart (Shishapangma and Cho Oyu), O'Brien decided to build on her passion for mountaineering and set herself the challenge of achieving the Explorers Grand Slam.

[20][21] For the sixth time in its 20-year history, Blue Origin successfully launched humans on a sub-orbital spaceflight on the New Shepard 22 mission.

The five humans that flew with O'Brien included Coby Cotton, Mário Ferreira, Clint Kelly III, Sara Sabry, and Steve Young, flying to a height of 107 km above Mean Sea Level (351,232 ft MSL).

[22] This was the first spaceflight of Blue Origin involving two female crew members, and Vanessa O'Brien carried the UN Women's flag.