Background Remote photoplethysmography (rPPG) can record vital signs (VSs) by detecting subtle changes in the light reflected from the skin. Lifelight (Xim Ltd) is a novel software being developed as a medical device for the contactless measurement of VSs using rPPG via integral cameras on smart devices. Research to date has focused on extracting the pulsatile VS from the raw signal, which can be influenced by factors such as ambient light, skin thickness, facial movements, and skin tone. Objective This preliminary proof-of-concept study outlines a dynamic approach to rPPG signal processing wherein green channel signals from the most relevant areas of the face (the midface, comprising the cheeks, nose, and top of the lip) are optimized for each subject using tiling and aggregation (T&A) algorithms. Methods High-resolution 60-second videos were recorded during the VISION-MD study. The midface was divided into 62 tiles of 20×20 pixels, and the signals from multiple tiles were evaluated using bespoke algorithms through weighting according to signal-to-noise ratio in the frequency domain (SNR-F) score or segmentation. Midface signals before and after T&A were categorized by a trained observer blinded to the data processing as 0 (high quality, suitable for algorithm training), 1 (suitable for algorithm testing), or 2 (inadequate quality). On secondary analysis, observer categories were compared for signals predicted to improve categories following T&A based on the SNR-F score. Observer ratings and SNR-F scores were also compared before and after T&A for Fitzpatrick skin tones 5 and 6, wherein rPPG is hampered by light absorption by melanin. Results The analysis used 4310 videos recorded from 1315 participants. Category 2 and 1 signals had lower mean SNR-F scores than category 0 signals. T&A improved the mean SNR-F score using all algorithms. Depending on the algorithm, 18% (763/4212) to 31% (1306/4212) of signals improved by at least one category, with up to 10% (438/4212) improving into category 0, and 67% (2834/4212) to 79% (3337/4212) remaining in the same category. Importantly, 9% (396/4212) to 21% (875/4212) improved from category 2 (not usable) into category 1. All algorithms showed improvements. No more than 3% (137/4212) of signals were assigned to a lower-quality category following T&A. On secondary analysis, 62% of signals (32/52) were recategorized, as predicted from the SNR-F score. T&A improved SNR-F scores in darker skin tones; 41% of signals (151/369) improved from category 2 to 1 and 12% (44/369) from category 1 to 0. Conclusions The T&A approach to dynamic region of interest selection improved signal quality, including in dark skin tones. The method was verified by comparison with a trained observer’s rating. T&A could overcome factors that compromise whole-face rPPG. This method’s performance in estimating VS is currently being assessed. Trial Registration ClinicalTrials.gov NCT04763746; https://clinicaltrials.gov/ct2/show/NCT04763746