[2][3] During President Obama’s first term, Palfrey worked as Senior Advisor for Jobs & Competitiveness in the White House Office of Science and Technology Policy.

In that role, he served as lead policy staffer on reform efforts[4] and also coordinated White House input into a report to Congress on the national strategy for innovation and competitiveness.

As the first Chief of the Health Care Division in the Office of the Massachusetts Attorney General,[14] Palfrey oversaw multi-million dollar consumer protection litigation and investigations relating to health insurance, pharmaceuticals, medical devices, healthcare providers and nursing homes.

In September 2017, Palfrey announced his campaign for lieutenant governor of Massachusetts,[15] stating that "we need leaders who will fight for good jobs and fair pay, work to reduce inequality and poverty, and stand up against attacks on our diverse and inclusive American values.

[17] Palfrey was defeated by Republican incumbent Karyn Polito in the general election held on November 6, 2018.

On January 21, 2021, Palfrey was sworn in by U.S. President Joe Biden to serve as Deputy General Counsel at the United States Department of Commerce.

His grandfather, John Gorham Palfrey, Jr. or the III (1919-1979), was a 1940 graduate of Harvard, served in World War II, was appointed to the Atomic Energy Commission by President John F. Kennedy, and was a professor at Columbia University from 1952 until his death in 1979 as well as dean of Columbia College from 1958 to 1962.

His 2nd great-grandfather was Joseph Edward Willard, lieutenant governor of Virginia and United States Ambassador to Spain.