A founder member of Matrix Chambers, he was appointed a Recorder of the Crown Court in 2001 and elected Chairman of the Criminal Bar Association in 2003. Later that year he became Director of Public Prosecutions (DPP), the first prominent defence lawyer to have been appointed to that post.

As DPP, he established the Counter Terrorism Division, the Organised Crime Division, the Special Crime Division and the Fraud Prosecution Service. He played a major role across Whitehall in the development of criminal justice policy, especially in relation to international treaties and jurisdictional issues, mutual legal assistance, extradition, terrorism and grave cross border crime.

Completing his term as DPP in 2008, he became a trustee of Index on Censorship, the leading free expression advocacy group, and was appointed Chair of Reprieve, the anti-death penalty organisation, in succession to Lord Bingham of Cornhill. He was appointed a Deputy High Court Judge in 2010, and became a member of the House of Lords in the same year.

Particularly well known for his ability to confront complex issues of detail with concision and clarity, he specialises in business and corporate crime and associated extraditions, financial regulatory work, market offences, export control violations, terrorism, and human rights law. His clients have included overseas governments, banks and financial institutions, international media organisations, prominent British and foreign corporations in all major sectors, and many private individuals at home and abroad.

He was a Visiting Professor of Law at the London School of Economics from 2009-2012, and he is currently a member of the Advisory Board of the Centre for Criminology at the University of Oxford. He has been a member of the Oxford University Law Faculty since 2012, and he lectures widely in UK and abroad, delivering the Annual F.A. Mann lecture, chaired by the Lord Chief Justice, in London in November 2013.

In July 2010, Ken Macdonald became a Liberal Democrat Peer and a member of the House of Lords, with the title Lord Macdonald of River Glaven QC. He was a member of the House of Lords Constitution Committee from 2012-2013.

At the invitation of Theresa May, the Home Secretary at the time, he oversaw a government review of counter terrorism legislation in January 2011.