Her interdisciplinary work on network theory and complex systems spans the fields of statistical physics, theoretical computer science and applied math, and has appeared in journals such as Science, PNAS, Physical Review Letters, and Nature Physics. She is a Fellow of the American Physical Society (class of 2016), a Fellow of the Network Science Society (class of 2019), and has received numerous honors such as the inaugural Euler Award of the Network Science Society in 2019, the 2018 ACM Test-of-Time award, and the 2017 UC Davis College of Engineering Outstanding Mid-Career Faculty Research Award. She has served on the editorial board of numerous international mathematics and physics journals and has organized key scientific meetings like NetSci 2014. She was a member of the World Economic Forum's Global Agenda Council on Complex Systems, and served as President of the Network Science Society, 2015-18.

D'Souza uses the tools of statistical physics and applied mathematics to develop mathematical models capturing the interplay between the structure and function of networks, including dynamical processes unfolding on networks. Her focus is on the abrupt onset of large-scale connectivity in networks, network synchronization behaviors and models of cascading failure. The general principles derived provide insights into the behaviors of real-world networks such as infrastructure networks and social networks, and opportunities to identify small interventions to control the self-organizing, collective behaviors displayed in these systems. She collaborates broadly with faculty within the college and in physics, statistics, political science and the Primate Center.