DePass served as the Executive Director for the New York City Environmental Justice Alliance from 1993 to 1997, the city's first environmental justice and health nonprofit. With the organization, she analyzed state and federal legislation and policy and how it affected NYC residents, co-founded the Northeast Environmental Justice Network, organized campaigns related to equity, and developed and implemented a youth mentorship program. During this time, she also served as the Principal Investigator for the New York/New Jersey Environmental Worker Training Program (1995-1997), where she administered the first regional Environmental Workforce Development Program for low-income and at-risk youth via partnerships and grants. DePass worked for the City of San Jose in California from 1998 to 2001 as the Environmental Compliance Manager, where she helped manage international commercial operations and oversaw compliance. Returning to New York, she was selected as a William Kunstler Racial Justice Fellow with the Center for Constitutional Rights in 2001, a highly competitive racial justice fellowship program focused on litigation for human rights cases. Through this program, she developed litigation in NYC and U.S. cases and provided legal counseling and training to communities of color. Following this fellowship, DePass served as the Senior Policy Advisor at the New Jersey Department of Environmental Protection for a year in 2002, helping with the state's equity policy and community-based initiatives to address community needs.

DePass joined the Ford Foundation in 2003 as the Program Officer for Economic Opportunity and Assets, where she developed and managed a grantmaking portfolio on the environment and community development. While at the foundation, she co-created the Gulf Coast Fund for Community Health and Ecological Renewal, which provided 4 million dollars in grants to communities after Hurricanes Katrina and Rita. In 2009, DePass started as an Assistant Administrator for the Office of International Tribal Affairs at the Environmental Protection Agency. She was appointed to the role by President Barack Obama and was responsible for the cooperation between the EPA, foreign nations, U.S. tribes, institutions, and donors. In addition, she oversaw the administration of $70 million in grants for tribal capacity building.

After departing the EPA in 2013, DePass became involved with academia, serving as the Dean and Tishman Professor at the Milano School of International Affairs, Management, and Urban Policy at The New School in New York. She served in this role for four and a half years until 2018 before becoming the Chief Executive Officer and President of the Meyer Memorial Trust, where she advanced racial, ethnic, and economic justice initiatives. Before beginning her role as President at DePass Paulson Advisors, DePass briefly worked as the Executive Director of Upside Tech Alliance in California from 2022 to 2023. Her current role at DePass Paulson Advisors helps provide philanthropic services to clients and supports organizations on their equity and inclusion journeys.