Purpose We estimate the association between forgetfulness to take medications as prescribed and polypharmacy and health-related quality of life (HRQoL) among a cohort of patients with hypertension, dyslipidemia or both in Greece during the COVID-19 pandemic. Methods A telephone survey of 1018 randomly selected adults was conducted in Greece in June 2020. Participants were included in the survey, if they (a) had a diagnosis of hypertension, dyslipidemia or both and (b) were on prescription treatment for these conditions. HRQoL was calculated using the short form (SF) -12 Patient Questionnaire. A multivariable generalized linear regression model (GLM) was used to estimate the association between forgetfulness and polypharmacy and HRQoL, controlling for sociodemographic and health-related covariates. Results Overall, 351 respondents met the inclusion criteria, of whom 28 did not fully complete the questionnaire (response rate: 92%, n = 323). Of those, 37% were diagnosed with hypertension only, 28% with dyslipidemia only, and 35% with both. Most reported good to average physical (64.1%) and mental health (48.6%). Overall, 25% indicated that they sometimes forget to take their prescribed medications, and 12% took two or more pills multiple times daily. Total HRQoL score was 68.9% (s.d. = 18.0%). About 10% of participants reported paying less attention to their healthcare condition during the pandemic. Estimates of multivariable analyses indicated a negative association between forgetfulness (− 9%, adjusted β: − 0.047, 95% confidence interval − 0.089 to − 0.005, p = 0.029), taking two or more pills multiple times daily compared to one pill once a day (− 16%, adjusted β: − 0.068, 95% confidence interval − 0.129 to − 0.008, p = 0.028) and total HRQoL. Conclusion Our results suggest that among adult patients with hypertension, dyslipidemia or both in Greece, those who forget to take their medications and those with more complex treatment regimens had lower HRQoL. Such patients merit special attention and require targeted approaches by healthcare providers to improve treatment compliance and health outcomes.