Though at the age of 14 she worked for teen magazines for girls but it was only in 2000 that she actively professed her profession as a presenter and her first show was S Club 7: Artistic Differences, a show on CITV, in which she played the role of Zoe. As a children’s entertainer, Willoughby presented Xchange, a children’s factual entertainment programme and hosted other shows for children including X-perimental and CBBC at the Fame Academy for CBBC but Holly & Stephen's Saturday Showdown was her first show as a children's entertainer aired on CITV. She was also honoured with BAFTA for her outstanding work as a TV presenter of children.
She presented the television show Dancing on Ice along with Phillip Schofield in which celebrities learn ice-dancing from their partnered professional dancers. Among the numerous ITV programs presented by Holly, some of them are Holly & Fearne Go Dating, Celebrity Wrestling: Bring It On, The Xtra Factor. Willoughby has presented Play to the Whistle, a sports-based panel show in 2015 on ITV.
She made a guest appearance in the film Keith Lemon: The Film and became a benefactor of Together for Short Lives, a charity in 2008. She was named among the 100 Sexiest Women by FHM and was also given Best Celebrity Cleavage award in 2012.