On 31 January 2010, she performed at the 52nd Grammy Awards with Jeff Beck in tribute to Les Paul and Mary Ford. She released her third studio album, Mayhem, in Ireland on 3 September 2010 – again reaching No. 1 in the Irish Album Charts – and in the United Kingdom on 4 October 2010.
She performed at a tribute concerts for Bill Wyman's 80th birthday, a live recorded concert for Jacques Dutronc, and a live recorded concert with and for Tony Biscontu for Sky Arts. In 2010 she performed with Jeff Beck honoring Les Paul at the Iridium Jazz Club in New York City, where the session was recorded for DVD and HBO and subsequently toured the U.S. with Jeff Beck for 5 weeks. In December 2011 she sold out 2 nights at O2 Dublin, with Bono making a surprise appearance as her guest. May was the surprise guest in Dublin for U2's homecoming show on the band's 2015 Innocence + Experience tour: Bono called her "the other queen of Ireland" as she came on stage to perform 'Desire', streamed live online to millions of viewers.