Upon graduation, he joined the management program at Morgan Guaranty Trust Company in New York City.

Jeffery initially accepted an offer from Davis Polk & Wardwell, before moving on to Goldman Sachs in 1983.

He served as a member of the United States National Security Council until 2005, as a Senior Director responsible for International Economic Affairs.

Currently Reuben Jeffery III serves as senior advisor at CSIS (Center for Strategic and International Studies).

In 2013, Jeffery was a signatory to an amicus curiae brief submitted to the Supreme Court in support of same-sex marriage during the Hollingsworth v. Perry case.