He is known for his development of analytical chemistry methods that are applied to air pollution monitoring and atmospheric chemistry research, and particularly the use of gas chromatography to measure volatile organic compounds (VOCs) and the composition of liquid fuels such as gasoline and diesel. He was the first person to use comprehensive gas chromatography (GCxGC) to establish the complexity of volatile organic compounds found in urban air, completed whilst on a research sabbatical at RMIT University, Australia. He held a lecturer position at the University of Leeds, as a joint appointment between the Schools of Chemistry and Earth & Environment before later moving to the Department of Chemistry at University of York in 2003.  He currently works in the [https://www.york.ac.uk/chemistry/research/wacl/ Wolfson Atmospheric Chemistry Laboratories] at York.
Between 2007 and 2012 Lewis worked part-time for the Natural Environment Research Council as their Theme Leader for research programmes in new technologies. Between 2008 and 2022 he was a science director at the National Centre for Atmospheric Science, with specific responsibility for air pollution and atmospheric composition research.
Lewis has published a number of commentary articles on air pollution science and policy in the UK, US and China. He has also made a number of appearances on TV and radio discussing vehicle emissions and indoor air pollution. He has been widely quoted as being skeptical about the value of air pollution removal technologies such as smog towers and roadside filter systems, and the wider sustainability of air filtration. He has raised potential problems associated with hydrogen for home heating, highlighting the negative impacts of emissions of NOx and the  concentration of those emissions in poorer neighbourhoods. With Prof. Chris Whitty and Dr Deborah Jenkins he published a future research needs strategy on Indoor Air Quality.
He has collaborated with Peter Edwards at York to evaluate low cost air pollution sensor technologies and with David Carslaw on diesel engine NOx emissions. Although primarily a chemist, he was named in a 2015 list of the World's 100 most influential analytical scientists. His research career was documented by the Science History Institute in 2011, part of series of interviews with atmospheric scientists.