From 2001 he presented on BBC Radio 5 Live: from his debut until 2009 on a daily afternoon programme, and since then until 2022 with Kermode and Mayo's Film Review on Fridays.

Between January 2010 to December 2018 he was the presenter of Simon Mayo Drivetime on BBC Radio 2, for the final six months with co-host Jo Whiley.

But as a result of a frequency deficiency in his left ear, he failed the required hearing test, and refocused his career on presenting.

Throughout his tenure on the breakfast show, which was based on a "zoo" format, Mayo was joined by news anchor Rod McKenzie and by a sidekick weather and travel presenter: first Carol Dooley, then Sybil Ruscoe, Jackie Brambles, and Dianne Oxberry.

Weather and travel news reader stand-ins include Mayo's Radio 1 colleague Lynn Parsons, Caron Keating (from Blue Peter and Songs of Praise), and Philippa Forrester (from CBBC).

The programme became known for various features, including On This Day in History, sound-tracked by a looped version of George Michael's "I Want Your Sex"; the long-running cryptic game The Identik-Hit Quiz, where Mayo and his co-hosts would act out a short scene which cryptically led listeners to the title of a hit song; and his Confessions feature where members of the public sought absolution for their (often frivolous or humorous) "sins".

Mayo had already presented the dilemma show Scruples for BBC television and had joined his Radio 1 colleagues on the host roster for Top of the Pops.

Due to frequent plays from Mayo, several unlikely hit singles reached the UK charts, including "Kinky Boots" by Patrick Macnee and Honor Blackman; "Donald Where's Your Troosers?"

For helping Monty Python have a hit with the latter, thirteen years after it first appeared on the soundtrack to The Life of Brian, Idle presented Mayo with a model bare foot, in the style of the animated version which used to end the opening titles to the TV show.

For a short while, he also presented an additional weekend show for the station on a Sunday afternoon, provisionally titled O Solomon Mayo, to cover for the absent Phillip Schofield, who was working in the West End.

His final show was on Friday 16 February 2001, and before signing off, he said: "One of the reasons I'm not going to 'do a DLT' is that I've nothing to complain about at all – though as I'll still be employed by the BBC it'd be a stupid thing to do.

The programme also featured Mayo's former Radio 1 sidekick Mark Kermode reviewing the new movie releases each Friday afternoon.

[24] In addition to his daily programme on 5 Live, from October 2001 to April 2007, Mayo hosted the Album Chart show each week for BBC Radio 2.

On 22 October that year, the station announced that Mayo would be leaving Radio 2 altogether after a backlash against the change, with Whiley moving back to an evening slot.

[26] As his opening theme Mayo used the 2003 recording by Jools Holland and Prince Buster of the 1948 song "Enjoy Yourself" by Carl Sigman and by Herb Magidson.

In May 2011, Mayo won a Sony Award for "Best Music Show" for his work and that of his team on the Radio 2 drive time slot.

[30] In addition to his daily programme on Scala, Mayo joined Greatest Hits Radio in September 2020, firstly taking over a weekly album show on Sundays from 1-4pm.

[32] Mayo presented Act Your Age, a panel game for BBC Radio 4, first broadcast on 27 November 2008.

[34] Between 1995 and 1998 Mayo presented a TV version of Confessions, based on the hit feature from his BBC Radio 1 breakfast and mid-morning shows.

Starting in 1999 he was the original presenter of National Lottery game show Winning Lines on BBC One until 2000 when he was replaced by Phillip Schofield in 2001.

In 2005 he presented a series The Big Dig on BBC TV about allotments in the Rhondda Valley contrasted with others in Highgate, London.

[38] The Guardian called it 'a great and thrilling book with an easy to read storyline that will help kids to understand elements!

Clare Clarke, for The Guardian, said: "With its huge, amorphous cast and little interior characterisation, its pages rich with Shakespeare’s poetry and the rousing gospel music for which Block 4 was reputedly renowned, the dialogue-heavy Mad Blood Stirring reads more like a first-draft film treatment than a finished novel.

The novelist John Boyne said: "Bristling with energy, written with passion, Mad Blood Stirring is a joy to read."