Between 2009 and 2013, Pepperdine co-wrote and starred (as Dr. Pippa Moore) in the BBC Four sitcom Getting On with Jo Brand and Joanna Scanlan. Brand, Scanlan, and Pepperdine won the 2010 Royal Television Society Award for Best Writing in Comedy. In 2010 the three also won the Writers' Guild of Great Britain award for Best Comedy. The show also won the award for Best Sitcom at the British Comedy Awards. For the third series, Brand, Scanlan and Pepperdine were nominated for the 2012 Royal Television Society Award and the BAFTA TV Awards for Best Writing in Comedy. Pepperdine went on to executive Produce and appear (reprising her role as Pippa Moore in the season three episode "Am I Still Me?") in HBO's three-season adaptation of the series.
From 2012-13, Pepperdine played the regular role of midwife Anna Nikolayevna in both series of A Young Doctor's Notebook.
In 2014, Pepperdine co-wrote, co-produced and starred in the improvisational comedy, Puppy Love, again with Scanlan. She played the character Naomi Singh who attends dog training classes run by Scanlan's character Nana V. Pepperdine said that the series is about "why the UK's 7.3 million wonders choose to get a dog "when the reality of mishap, adventure and tribulation is often more than they bargained for"". The Independent described the show as being a "very funny...slow-build, slyly smart" character comedy.
In 2014, Pepperdine played Harry Hill's housekeeper Mrs Flittersnoop in The Incredible Adventures of Professor Branestawm on BBC One.
Pepperdine has regularly collaborated with comedian and writer Julia Davis and credits her as being the "funniest person I know". She starred in series one of Davis' dark comedy Nighty Night (2004) as Mrs. Horner; the Sky Atlantic series Camping (2016) as overbearing mother and wife Fiona; and Belinda, the ineffectual therapist, in the Sky Atlantic sitcom Sally4Ever (2018).
From 2013-2015, Pepperdine played Gwen in Jessica Hynes' Up the Women, a sitcom about women in the Suffragette movement. She wore a pair of false teeth, which she later used for her role as Princess Ann in The Windsors.
Pepperdine is also known for her recurring role of Princess Anne in The Windsors (2016–2023). Fi Glover, on her BBC podcast Fortunately... with Fi and Jane, described Pepperdine's portrayal as "riveting, just riveting". Pepperdine described it as one of "my favourite jobs ever to do, because it's such fun".
In 2017, Pepperdine collaborated with Ellie White on Summer Comedy Shorts: Vicki Pepperdine & Ellie White's Summer for Sky Arts. The film was about a female Morris dancing troupe in the English countryside. Pepperdine played the character of Alison.