Mary Lewis completed a BA in archaeology at the University of Leicester in 1992 and the attended the University of Bradford where she studied for an MSc in osteology and a PhD in bioarchaeology. Her thesis was titled The impact of urbanisation and industrialisation in medieval and post-medieval Britain: an assessment of the morbidity and mortality of non-adult skeletons from the cemeteries of two urban and two rural sites in England and supervised by Charlotte Roberts. While at Bradford, Lewis and Roberts examined human remains excavations from the church of St Helen-on-the-Walls in York. Looking at 2,000 skeletons, it was the first study to use archaeological evidence to examine how the environment effects health. They found that people living in the industrial area of medieval York were more likely to suffer from sinus infections than people from rural areas with less air pollution. Lewis joined the University of Reading in 2004. Lewis conducted the first osteological study of a body which had been subjected to hanging, drawing, and quartering. The results were published in the 2008 edition of Antiquity and shortlisted for the Ben Cullen Prize. Along with Reading colleagues Gundula Müldner and Hella Eckardt, Lewis took part a research project to examine the archaeological evidence for immigration in Roman Britain and how these people interacted. The project, which began in 2007, was funded by the Arts and Humanities Research Council and the results were used to inform displays at the Yorkshire Museum and create educational resources for Key Stage 2 pupils. The team produced the 'Romans Revealed' website aimed at school children to give more information on Roman Britain, broadening the history taught in schools which usually focuses on men from Italy. The AHRC provided additional funding while the Runnymede Trust also supported the project to help the website addressed what children wanted to learn about. Between 2011 and 2014, Lewis worked with Janet Montgomery and Fiona Shapland on the Leverhulme-funded project 'Adolescence, Migration and Health in Medieval England: the osteological evidence'. The project examined remains from people aged 10–25 from cemeteries in St Mary Spital and Barton-on-Humber. In 2016, Lewis won the Society for Medieval Archaeology's Martyn Jope Award for "the best novel interpretation, application of analytical method or presentation of new findings" published in that year's volume of Medieval Archaeology.
