He joined the Center for Strategic and Budgetary Assessments as a senior fellow for maritime affairs. He later became the CSBA's vice president for strategic studies. He also took a position as an adjunct professor at George Washington University, teaching defense analysis and roles and missions of the armed forces. During this period, Work wrote and spoke extensively on naval and marine strategy. He also directed and analyzed war games for the Office of Net Assessment and for the Office of the Secretary of Defense. He participated in the Quadrennial Defense Review in 2006. Work's work has focused on defense strategy; proposals to restructure the Department of Defense; and maritime affairs.
During the presidential transition of Barack Obama, Work was a member of the Department of Defense Transition Team, focusing on the transition at the United States Department of the Navy. President Barack Obama nominated Work as Under Secretary of the Navy and Work was confirmed by the United States Senate on May 19, 2009. Work has criticized former Defense Secretary Donald Rumsfeld for assuming that the United States would always have an advantage in guided weapons and, as such, be able to quickly defeat any foe. In July 2011, Work called into question the navy's plans for the Lockheed Martin F-35 Lightning II, asking if the numbers or types could be reduced in favor of more unmanned systems. In 2012, after submitting a budget request that reduced submarine construction, Work said that only a submarine could operate in the Taiwan Strait during a conflict with China. In 2013, the Center for a New American Security announced that Work would be their new CEO as of April 22, 2013.
On February 7, 2014, President Obama nominated Work to become Deputy Secretary of Defense. In October 2014, Deputy Secretary Work instructed the Defense Business Board to hire consultants from McKinsey & Company to identify wasteful spending. McKinsey discovered DoD was spending $134 billion, 23% of its total budget, on back-office work, and that the back-office bureaucracy staff of over one million people was nearly as great as the number of active duty troops. On January 22, 2015, the board then voted to recommend adoption of McKinsey's five-year plan to cut $125 billion in waste. However, after Secretary Chuck Hagel was replaced by Ash Carter the next month, Deputy Secretary Work expressed his concerns that any gain from savings achieved would then be removed from the defense budget by Congress. Under Secretary Frank Kendall III argued that he could not achieve any efficiencies and, instead, that he needed to hire 1,000 more staff. Secretary Carter then replaced the board chairman, classified the McKinsey results as secret, and removed the report from public websites. When James Mattis became defense secretary in January 2017, he asked Work to remain as deputy in order to complete several tasks, including preparing an amendment for additional funding in fiscal year 2017 and preparing the fiscal year 2018 budget for submittal in May 2017. This may have marked the first time in history when the top three posts at the Pentagon – secretary, deputy secretary, and Chairman of the Joint Chiefs – were held by Marines.
After retiring as Deputy Defense Secretary, Work in 2018 criticized Google and its employees for, in his view, stepping into a moral hazard for themselves as not continuing Pentagon's artificial intelligence project while helping the autocratic communist China's AI technology that could be used against the United States in a conflict. He described Google as hypocritical, given it has opened an AI center in China and said "nything that’s going on in the AI center in China is going to the Chinese government and then will ultimately end up in the hands of the Chinese military. I didn’t see any Google employee saying, ‘Hmm, maybe we shouldn't do that.'"
