Earth System models (ESMs) are effective tools for investigating the water-energy-food system interactions under climate change. In this presentation, I will introduce research efforts at the Pacific Northwest National Laboratory towards quantifying impacts of LULCC on the water-energy-food nexus in a changing climate using an integrated regional Earth system modeling framework: the Platform for Regional Integrated Modeling and Analysis (PRIMA). Two studies will be discussed to showcase the capability of PRIMA: (1) quantifying changes in terrestrial hydrology over the Conterminous US (CONUS) from 2005 to 2095 using the Community Land Model (CLM) driven by high-resolution downscaled climate and land cover products from PRIMA, which was designed for assessing the impacts of and potential responses to climate and anthropogenic changes at regional scales; (2) applying CLM over the CONUS to provide the first county-scale model validation in simulating crop yields and assessing associated impacts on the water and energy budgets using CLM. The studies demonstrate the benefits of incorporating and coupling human activities into complex ESMs, and critical needs to account for the biogeophysical and biogeochemical effects of LULCC in climate impacts studies, and in designing mitigation and adaptation strategies at a scale meaningful for decision-making. Future directions in quantifying LULCC impacts on the water-energy-food nexus under a changing climate, as well as feedbacks among climate, energy production and consumption, and natural/managed ecosystems using an Integrated Multi-scale, Multi-sector Modeling framework will also be discussed.