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Background: Rapid development and implementation of vaccines constituted a crucial step in containing the COVID-19 pandemic. A comprehensive understanding of physiological responses to these vaccines is important to build trust in medicine., Objective: This study aims to investigate temporal dynamics before and after COVID-19 vaccination in 4 physiological parameters as well as the duration of menstrual cycle phases., Methods: In a prospective trial, 17,825 adults in the Netherlands wore a medical device on their wrist for up to 9 months. The device recorded their physiological signals and synchronized with a complementary smartphone app. By means of multilevel quadratic regression, we examined changes in wearable-recorded breathing rate, wrist skin temperature, heart rate, heart rate variability, and objectively assessed the duration of menstrual cycle phases in menstruating participants to assess the effects of COVID-19 vaccination., Results: The recorded physiological signals demonstrated short-term increases in breathing rate and heart rate after COVID-19 vaccination followed by a prompt rebound to baseline levels likely reflecting biological mechanisms accompanying the immune response to vaccination. No sex differences were evident in the measured physiological responses. In menstruating participants, we found a 0.8% decrease in the duration of the menstrual phase following vaccination., Conclusions: The observed short-term changes suggest that COVID-19 vaccines are not associated with long-term biophysical issues. Taken together, our work provides valuable insights into continuous fluctuations of physiological responses to vaccination and highlights the importance of digital solutions in health care., International Registered Report Identifier (irrid): RR2-10.1186/s13063-021-05241-5., (©Andjela Markovic, Vladimir Kovacevic, Timo B Brakenhoff, Duco Veen, Paul Klaver, Marianna Mitratza, George S Downward, Diederick E Grobbee, Maureen Cronin, Brianna M Goodale, COVID-19 Remote Early Detection (COVID-RED) consortium. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 31.07.2024.)