Background Variations in body temperature are highly informative during an illness. To date, there are not many adequate studies that have investigated the feasibility of a wearable wrist device for the continuous monitoring of body surface temperatures in humans. Objective The objective of this study was to validate the performance of HEARThermo, an innovative wearable device, which was developed to continuously monitor the body surface temperature in humans. Methods We implemented a multi-method research design in this study, which included 2 validation studies—one in the laboratory and one with human subjects. In validation study I, we evaluated the test-retest reliability of HEARThermo in the laboratory to measure the temperature and to correct the values recorded by each HEARThermo by using linear regression models. We conducted validation study II on human subjects who wore HEARThermo for the measurement of their body surface temperatures. Additionally, we compared the HEARThermo temperature recordings with those recorded by the infrared skin thermometer simultaneously. We used intraclass correlation coefficients (ICCs) and Bland-Altman plots to analyze the criterion validity and agreement between the 2 measurement tools. Results A total of 66 participants (age range, 10-77 years) were recruited, and 152,881 completed data were analyzed in this study. The 2 validation studies in the laboratory and on human skin indicated that HEARThermo showed a good test-retest reliability (ICC 0.96-0.98) and adequate criterion validity with the infrared skin thermometer at room temperatures of 20°C-27.9°C (ICC 0.72, P<.001). The corrected measurement bias averaged –0.02°C, which was calibrated using a water bath ranging in temperature from 16°C to 40°C. The values of each HEARThermo improved by the regression models were not significantly different from the temperature of the water bath (P=.19). Bland-Altman plots showed no visualized systematic bias. HEARThermo had a bias of 1.51°C with a 95% limit of agreement between –1.34°C and 4.35°C. Conclusions The findings of our study show the validation of HEARThermo for the continuous monitoring of body surface temperatures in humans.