OBJECTIVE: The impact of COVID-19 vaccination on parental and childhood stress levels has not been thoroughly investigated. Our aim was to explore the above relationship and identify factors that may influence the dissemination of stress within the family during the pandemic. SUBJECTS AND METHODS: A cross-sectional e-survey was conducted among a nationwide sample of parents in May 2021 in Greece. Parental stress was assessed using the Perceived Stress Scale (PSS) and the Revised Impact of Event Scale (IES-R) tools. Childhood mental well-being was evaluated with the Children's Revised Impact of Event 13 (CRIES 13) scale. RESULTS: 1,703 unique questionnaires were analyzed; 19.5% of responders were completely vaccinated, 23.7% were partially vaccinated, 38.3% were awaiting vaccination, and 18.5% were classified as vaccine-hesitant (15.2% would delay, and 3.3% refused the vaccination). Stress levels were significantly lower in completely or partially vaccinated parents than in vaccine-hesitant ones (p<0.001 for PSS/IES-R). Vaccination status emerged as a strong and independent predictor of PSS and IES-R. A significant decrease in PSS and IES-R scores was observed in 991 participants between March 2020 and May 2021 (p<0.001 for PSS/IES-R). Vaccine uptake was associated with lower PSS and IES-R scores, irrespective of the phase of the pandemic or other sociodemographic factors. The CRIES 13 score of the participant's children (n=2,969) was 19.4 ±14.9 and positively correlated with the PSS and IES-R scores. Children whose parents were vaccinated had lower stress levels than those of vaccine-hesitant parents (p<0.001). CONCLUSIONS: Parental vaccination against COVID-19 is a significant stress and anxiety predictor for both parents and their offspring. Parental and childhood stress levels were correlated, while the effect of vaccination was independent of the pandemic phase. The campaigns to promote vaccine uptake against COVID-19 should also highlight its potential benefit on the psychological well-being of the family.