[7] In 1945, William Zimdin [de], an Estonian immigrant to the United States and businessman, began sending thousands of relief parcels to relatives, friends, and former employees in Europe to help with the aftermath of World War II.

[20] The organization also donated approximately $23.5 million to support the operations of health groups, including hiring more staff and converting buildings to solar energy and battery backup microgrids to better withstand disasters.

[26] The organization manages logistics and distribution through enterprise systems that include SAP, Esri, and in-kind transportation support from FedEx.

[30] Solar panels are integrated with battery storage and generators to keep the headquarters running for up to six months in the face of a disaster and to store temperature-sensitive medications like insulin and vaccines.

[22] In 2013, Direct Relief launched a program in partnership with Basic Health International to screen and treat women in Haiti for cervical cancer.

[78] In May 2020, Direct Relief announced that it was partnering with FedEx Cares to ship personal protective equipment to underserved communities around the US.

[80] Direct Relief provides support to local and international wildfire incidents, including masks, vehicles, and funds to advance firefighter technology.

In July 2019, the organization released an analysis of which small towns in California could be the hardest hit by a fast-moving wildfire based on the numbers of low-income, immobile, aging, or disabled people in the community.

[89] Direct Relief delivers medical aid to people in high-need areas worldwide by supporting partners that provide child and maternal health services through the full process of pregnancy.

In 2017, Direct Relief distributed 300 midwife kits to fourteen partners in seven countries in the Caribbean, Southeast Asia, and Sub-Saharan Africa, supporting 15,000 safe births.