Garrett has had an extensive music career. A graduate of the Royal Academy of Music and an alumna of the prestigious National Opera Studio, she won the Decca Prize of the Kathleen Ferrier Award in 1979, thereby launching her career. Her professional debut, in 1979, was as Amor in Orontea at the music festival in Batignano. She subsequently sang, in 1980, Alice in Le comte Ory at the London Coliseum and Dorinda in Orlando at the Wexford Festival, in 1981, also at Wexford, the title role in Zaide, in 1982 Sophie in Werther with Opera North and in 1984 Damigella in L'incoronazione di Poppea at Glyndebourne. From 1984, as principal Soprano at English National Opera, she became well known for her performances in productions of the operas Serse, Le Nozze di Figaro, Così fan tutte and Die Fledermaus.

Other recordings include complete audio operas: Mozart's The Magic Flute (Papagena) conducted by Sir Charles Mackerras, Mozart's Così fan tutte (Despina), also conducted by Mackerras and Yum-Yum in the audio and video recordings of the Jonathan Miller production of The Mikado from ENO. She appears on two other DVDs of complete works from English National Opera, Handel's Ariodante (Dalinda) and Xerxes (Atalanta). In the video of the 1984 Glyndebourne L'incoronazione di Poppea under Raymond Leppard, she sings Nutrice and Valletto.

Garrett married in May 1991: her husband, Peter, is a GP in Muswell Hill. They have a son, Jeremy, and a daughter, Chloe. The family lives in north London.

Garrett has performed at several FA Cup Finals, including the 2000 Final, the last to be held at the old Wembley Stadium, the 2007 final held at new Wembley Stadium (alongside Sarah Brightman), and the 2008 Final (alongside Katherine Jenkins).

In 2002 Garrett was appointed a CBE for her services to music.

On Christmas Day 2004 BBC Two broadcast Lesley Garrett – Music from the Movies, co-starring her with Ruthie Henshall, Michael McCarthy with the backing of the Opera North orchestra. The programme was recorded at the Opera In The Park concert which had taken place in the grounds of Temple Newsam, West Yorkshire on 19 July 2003.

In 2004 Garrett was one of the participants in the first series of the Celebrity talent contest Strictly Come Dancing; she and her dance partner Anton du Beke finished third. In the same year she took part in the BBC's Who Do You Think You Are?, a genealogy documentary series, in which she journeyed through her home town of Thorne in search of her family history. Garrett was delighted to discover that the musical gene stretched far back and had run in her family for several generations. Garrett is a veteran of Dictionary Corner on the Channel 4 game show Countdown and in June 2005 it was thought that she was to become one of the show's rotating guest hosts while Richard Whiteley was recovering from illness. After Whiteley's death, however, the plan for rotating guest hosts was abandoned and Des Lynam took the role for the next fifteen months. Garrett did not appear on Countdown again until October 2009.

In February 2005 Garrett was selected to be one of the judges for BBC's Comic Relief does Fame Academy, and in May she hosted and sang at the 2005 Classical BRIT Awards at the Royal Albert Hall on ITV. In 2006 Garrett was a regular panellist on the ITV daytime show Loose Women; she featured there again in 2009 and 2010, before returning in May 2014. Garrett also appeared on This Morning and Loose Women in 2007, to perform a song from her latest album When I Fall in Love. She also continued the post as a judge on Comic Relief Does Fame Academy in 2007. Garrett currently presents a show on the British classical radio station Classic FM.

Over four weeks, beginning on 30 November 2008, she presented the Sunday morning BBC1 programme Christmas Voices.

In November 2010 she joined a long line of panellists on Five's The Wright Stuff.

Along with Larry Lamb, Garrett presented a short BBC series entitled When Royals Wed to celebrate the wedding of Prince william and Catherine Middleton in April 2011.

She also sang the British national anthem on the Champs-Élysées in Paris in 2012 after Bradley Wiggins became the first Briton to win the Tour de France, though her performance was not universally appreciated.

On 30 May 2014 she made her return to the ITV daytime show Loose Women. It was announced on the programme that she would become a regular panellist again.

She created the role of Val in Pleasure, the first opera by Mark Simpson, directed by Tim Albery and premiered at the Howard Assembly Room by Opera North, in April 2016.

On 10 Sep 2017 she featured on the TV show 'My Life on a Plate' when a Brian Turner accompanied her on a trip to key locations from her childhood in Yorkshire, where she was taught by her parents to make the most out of what was available. The chef then creates two dishes that weave nostalgia and the taste of home together.

Garrett featured in an episode of the BBC's popular genealogy programme, Who Do You Think You Are?, in which she explored her family's Yorkshire origins. She found out about the Musicians in her family: her maternal grandfather made a living playing the piano with a small orchestra that accompanied silent films at cinemas in and around Sheffield. A great-grandfather was a travelling musician, who travelled across Northern England in the 19th century, playing to workers in pubs and clubs. During World War I he entertained troops on the piano.