Nicholls' father was Sir Harmar Nicholls, later Lord Harmar-Nicholls, the former Conservative MP for Peterborough (1950–1974) and MEP for Greater Manchester South (1979–1984), and subsequently a life peer; she is thus entitled to be addressed as "The Honourable Susan Nicholls". Nicholls is married to Mark Eden, alongside whom she acted for a time in Coronation Street when he played the role of Alan Bradley.

Notable roles for Nicholls prior to Coronation Street include, Crossroads from 1964–68 and The Fall and Rise of Reginald Perrin from 1976–79. She also appeared on Broadway in the 1974 revival of the comedy London Assurance.

Nicholls first became known as Marilyn Gates on Crossroads, a role she played from 1964-68. A song she first sang on the programme, "Where Will You Be?", charted on 3 July 1968, eventually reaching number 17 in the UK Singles Chart.

Nicholls' second single was less successful and she embarked on a career in a cabaret, performing her solo act all over the country. She returned to the stage in a variety of popular plays and pantomimes. During the 1970s, she had two very different stints abroad. In Vienna she sang between strip acts at a nightclub while in 1976 she toured America and Canada with the Royal Shakespeare Company in London Assurance, finishing with a six-week run on Broadway.

She played the role of the secretary, Joan Greengross (later Webster and Millbeck) in the sitcom The Fall and Rise of Reginald Perrin (1976–79) and its sequel The Legacy of Reginald Perrin (1996), as well as Nadia Popov in Rentaghost and Mrs Muddle in Pipkins (1973). She has played Audrey in Coronation Street as an occasional visitor since April 1979, and a full-time permanent character since 1985.

In 2011 while watching an episode of Coronation Street, Anna Bianconi-Moore, a nurse at the dermatology department at Addenbrooke's Hospital in Cambridge, noticed a mole on Sue Nicholls' shoulder. The nurse contacted the show immediately via e-mail to express her concerns. Nicholls' was seen by Coronation Street's in-house medical team, and later referred to a skin cancer specialist, where she was diagnosed with malignant melanoma. After the mole was surgically removed ITV contacted Bianconi-Moore to inform her on the situation, and she was invited to the Coronation Street set to meet Nicholls.