Eli and Peyton Manning volunteered in the wake of Hurricane Katrina. The Mannings assisted in the delivery of 30,000 pounds (14,000 kg) of water, Gatorade, baby formula, pumice, and pillows to the people of New Orleans.

After touring the University of Mississippi Medical Center's Blair E. Batson Hospital for Children, Manning undertook a 5-year campaign in 2007 to raise $2.5 million for the construction of "The Eli Manning Children's Clinics" at the children's hospital. Manning said in 2007, "I am humbled by the work they do and am honored to make this five-year commitment to help raise funds to build this state-of-the-art clinic that will serve Mississippi families for years to come."

In 2009, Eli, Peyton, and Archie co-authored a children's book entitled Family Huddle, which describes in simple text and pictures how the three Manning brothers played football as young boys (Scholastic Press; illustrations by Jim Madsen).

In 2010, as a result of the Deepwater Horizon oil spill, Manning appeared in a commercial to raise awareness for the spill. Also starring in the commercial were Sandra Bullock, Peyton Manning, Jack Del Rio, Drew Brees, Terry Bradshaw, Emeril Lagasse, James Carville, Blake Lively, and John Goodman.

Eli Manning has for five years been the host of Guiding Eyes for the Blind's Golf Classic, the oldest and largest charity golf event in Westchester County, NY. Guiding Eyes is a nonprofit guide dog school serving the blind and visually impaired from around the world, as well as children on the autism spectrum. Eli hosts the event because of the participation of a close family friend, Patrick Browne, Jr., who became blind as an adult and who participates in the blind golfer tournament held the day before the sponsor-support charity outing. The Golf Classic raises more than $500,000 annually.