Health care systems are rapidly deploying digital tools for disease management; however, few studies have evaluated their usability by vulnerable populations. To understand the barriers to app usage among vulnerable populations, we employed user-centered design (UCD) methods in the development of a new text messaging app.The study aimed to describe variations in patients' engagement in the app design process, focusing on limited health literacy (LHL), limited English proficiency (LEP), and limited digital literacy (LDL).We conducted 20 in-depth semistructured interviews with primary care patients at a public health care system, used open-ended discussions and card sorting tasks to seek input about mobile phones and text messaging, and used open coding to categorize the patterns of mobile phone usage and to evaluate engagement in the card sorting process. We examined qualitative differences in engagement by examining the extensiveness of participant feedback on existing and novel text messaging content and calculated the proportion of patients providing extensive feedback on existing and novel content, overall and by health literacy, English proficiency, and digital literacy.The average age of the 20 participants was 59 (SD 8) years; 13 (65%) were female, 18 (90%) were nonwhite, 16 (80%) had LHL, and 13 (65%) had LEP. All had depression, and 14 (70%) had diabetes. Most participants had smartphones (18/20, 90%) and regularly used text messaging (15/20, 75%), but 14 (70%) of them reported having difficulty texting because of inability to type, physical disability, and low literacy. We identified 10 participants as specifically having LDL; 7 of these participants had LEP, and all 10 had LHL. Half of the participants required a modification of the card sorting activity owing to not understanding it or not being able to read the cards in the allotted time. The proportion of participants who gave extensive feedback on existing content was lower in participants with limited versus adequate English proficiency (4/13, 30% vs 5/7, 71%), limited versus adequate health literacy (7/16, 44% vs 3/4, 75%), and limited versus adequate digital literacy (4/10, 40% vs 6/10, 60%); none of these differences were statistically significant. When examining the proportion of patients who gave extensive feedback for novel messaging content, those with LHL were less engaged than those with adequate health literacy (8/16, 50% vs 4/4, 100%); there were no statistical differences by any subgroup.Despite widespread mobile phone use, digital literacy barriers are common among vulnerable populations. Engagement in the card sorting activity varied among participants and appeared to be lower among those with LHL, LEP, and LDL. Researchers employing traditional UCD methods should routinely measure these communication domains among their end-user samples. Future work is needed to replicate our findings in larger samples, but augmentation of card sorting with direct observation and audiovisual cues may be more productive in eliciting feedback for those with communication barriers.