During the break between her junior and sophomore year in college, Henderson worked as an intern for World Leaders Entertainment, where she worked on the third season of the animated television series Venture Bros.. She began her work on that program doing storyboards for animatics, which involved preparing backgrounds by converting background artist Denny Finkel’s line drawings into Flash animation so that they could then be sent to Korea to be painted. It was her first time using a Cintiq drawing tablet. That season would later premiere in June 2008.
The following year, during the break between her sophomore and junior year, Henderson worked on live-action film Underdog, which was released in 2007.
Henderson later worked an art director in the video game industry.
Henderson illustrated Marvel Comics’ Squirrel Girl for its first 37 issues before leaving the series in March 2018, although she continued to illustrate the series’ covers. Graeme Virtue of Guardian praised her artwork on the series, saying, “The real selling point is the gorgeous, cartoon-influenced art by EricaHenderson, which looks like nothing else Marvel is putting out at the moment”.