The most commonly used method to assess peripheral oxygen saturation (SpO2) in clinical practice is pulse oximetry. The smartwatch Apple Watch 6 was developed with a new sensor and an app that allows taking on-demand readings of blood oxygen and background readings, day and night. The present study aimed to assess the feasibility and agreement of the Apple Watch 6 compared with a standard SpO2 monitoring system to assess normal and pathological oxygen saturation. We recruited study participants with lung disease or cardiovascular disease and healthy subjects. A total of 265 subjects were screened for enrolment in this study. We observed a strong positive correlation between the smartwatch and the standard commercial device in the evaluation of SpO2 measurements (r = 0.89, p < 0.0001) and HR measurements (r = 0.98, p < 0.0001). A very good concordance was found between SpO2 (bias, −0.2289; SD, 1.66; lower limit, −3.49; and upper limit, 3.04) and HR (bias, −0.1052; SD, 2.93; lower limit, −5.84; and upper limit, 5.63) measured by the smartwatch in comparison with the standard commercial device using Bland–Altman analysis. We observed similar agreements and concordance even in the different subgroups. In conclusion, our study demonstrates that the wearable device used in the present study could be used to assess SpO2 in patients with cardiovascular or lung diseases and in healthy subjects.