Knowles began his career in 1991 with a research fellowship at St Catharines College, Cambridge, before moving to New Zealand to work as a research and consultancy metallurgist for Industrial Research Ltd between 1993 and 1995. He then returned to the University of Cambridge in 1995 to take up a post as lecturer in Mechanical Properties of Materials, and was also appointed assistant director of Research of the Rolls-Royce University Technology Centre.  His research at that time focussed on fatigue and creep in nickel based superalloys including high stress low' temperature creep anisotropy in single crystals. In 2001 Knowles returned to New Zealand to take up the role of CTO at MPT Solutions, where he continued to publish academic papers with a developing interest in crystal plasticity.  In 2006 he was appointed Global Research Leader for Materials at Shell Global Solutions, based in Amsterdam looking into materials for LNG and gas to liquid technologies.  In 2010, he moved to Atkins as their materials authority in the energy sector, focussing on offshore wind turbine foundations and nuclear Advanced Gas Reactors.  In 2016 he took up a post at the University of Bristol as Professor of Nuclear Engineering, and co-director of the South West Nuclear Hub.
Knowles was named Chief Executive of the Henry Royce Institute for advanced materials research in 2019.  He has continued his research as the principal investigator on the Sindri prosperity partnership EPSRC project, working with a number of university partners alongside EDF and UKAEA, which is focussed on characterising and modelling the meso to macro scale mechanics of alloys.  In particular, he is interested in researching the use of data-centric methods to interrogate and describe material mechanical behaviour which can then be used to predict the condition of components of nuclear power plants.