Despite the proliferation of eHealth interventions, such as web portals, for health information dissemination or the use of mobile apps and wearables for health monitoring, research has shown that underserved groups do not benefit proportionately from these eHealth interventions. This is largely because of usability issues and the lack of attention to the broader structural, physical, and psychosocial barriers to technology adoption and use. The objective of this paper is to draw lessons from a decade of experience in designing different user-centered eHealth interventions (eg, web portals and health apps) to inform future work in leveraging technology to address health disparities. We draw these lessons from a series of interventions from the work we have done over 15 years in the Viswanath laboratory at the Dana-Farber Cancer Institute and Harvard TH Chan School of Public Health, focusing on three projects that used web portals and health apps targeted toward underserved groups. The projects were the following: Click to Connect, which was a community-based eHealth intervention that aimed to improve internet skills and health literacy among underserved groups by providing home access to high-speed internet, computer, and internet training classes, as well as a dedicated health web portal with ongoing technical support; PLANET MassCONECT, which was a knowledge translation project that built capacity among community-based organizations in Boston, Lawrence, and Worcester in Massachusetts to adopt evidence-based health promotion programs; and Smartphone App for Public Health, which was a mobile health research that facilitated both participatory (eg, surveys) and passive data (eg, geolocations and web-browsing behaviors) collection for the purpose of understanding tobacco message exposure in individuals’ built environment. Through our work, we distilled five key principles for researchers aiming to design eHealth interventions for underserved groups. They are as follows: develop a strategic road map to address communication inequalities (ie, a concrete action plan to identify the barriers faced by underserved groups and customize specific solutions to each of them), engage multiple stakeholders from the beginning for the long haul, design with usability—readability and navigability—in mind, build privacy safeguards into eHealth interventions and communicate privacy–utility tradeoffs in simplicity, and strive for an optimal balance between open science aspirations and protection of underserved groups.