Health literacy and hypertension control are more limited in rural U.S. residents relative to metropolitan counterparts. Contemporary hypertension guidelines advocate for health education and home blood pressure monitoring (HBPM) to advance hypertension management. We conducted a preliminary assessment of the effect of health literacy on utilization of a virtual coaching agent, a computerized animation to converse with patient users, to promote HBPM. We recruited individuals from primary care practices in rural Pennsylvania; measured health literacy with the Brief Health Literacy Screen (BRIEF) and the Newest Vital Sign (NVS); and monitored virtual coach interactions and frequency of HBPM for 26 weeks. Participants (n = 59; age 58 ± 15 years, 59% female, 71% < bachelor's degree) had 1.03 ± 1.05 agent interactions and 5.4 ± 3.6 HBPM sessions/week over 1487 total participant-weeks. Virtual coach use was associated with greater odds of achieving the target HBPM frequency of 4 readings per week (Odds Ratio [OR] per interaction, 1.10 [95% Confidence Interval [CI]: 1.01-1.20]). This association was moderated by health literacy as measured by the BRIEF (interaction p = 0.01); with a greater magnitude among those with limited/marginal literacy (OR 1.31 per interaction, 95% CI: 1.10-1.57). NVS did not significantly moderate the association (interaction p = 0.12). In this preliminary cohort, use of a virtual coach was associated with higher adherence to HBPM in individuals with limited health literacy as measured by the BRIEF. Our results suggest that the frequency of virtual coach interactions is strongly associated with improvement in HBPM adherence among individuals with limited health literacy compared with those with adequate health literacy. Clinical Trial Registration: NCT05546931.