Denis Keefe was born 29 June 1958, the son of Dr John Victor Keefe and Dr Oonagh Rose Keefe (née McAleer). He was educated at Campion School, Hornchurch; Churchill College, University of Cambridge (MA Classics); Hertford College, University of Oxford and Malmö University. In 1983, he married Catherine Ann Mary Wooding, having three sons and three daughters.

Keefe joined the Diplomatic Service in 1982 and his diplomatic career included: Foreign and Commonwealth Office, 1982–84; Second Secretary, Prague [Czechoslovakia], 1984–88; First Secretary: FCO, 1988–92; Nairobi [Kenya], 1992–95; Deputy Head, South Asian Department, FCO, 1996–97; Head, Asia-Europe Meeting Unit, 1997–98; Deputy Head of Mission, Prague [Czech Republic], 1998–2002; on secondment as Counter Terrorism Strategy Team Leader, Cabinet Office, 2002–03; Head, China Hong Kong Department, 2003–04, and Far Eastern Group, 2004–06, FCO; Ambassador to Georgia, 2007–10; Deputy Head of Mission, Moscow [Russia], 2010–14; Ambassador to Serbia, 2014–19; Director, Faculty for National Security, Royal College of Defence Studies, 2019-22.