Her interest in acting was ignited after her appearance in a Jaywalking segment on The Tonight Show with Jay Leno gained network attention.

In 2007, Sher played a student attending Harbor High in the final season of the Fox drama series The O.C.. She also appeared in the 2001 short film Stuck and television commercials for Capital One and Fruity Pebbles.

From 2009 to 2018, Sher starred in the ABC comedy series The Middle as Sue Heck, a quirky but optimistic teenager.

[5][6] On May 30, 2018, it was reported that a spin-off focused on Eden Sher's character Sue Heck was in the works at ABC and nearing a pilot order with the goal to launch in midseason.

[7][8] On July 20, 2018, in an interview with TVLine's Michael Ausiello, Sher revealed that the network had ordered a pilot for the potential series, to possibly launch in early 2019.