Exposure to heat waves (HW) and warm days (WD) is an emerging public health concern. This study assesses the short-term effects of HW and WD on mortality and morbidity in the most populated city of Chile (Santiago de Chile). A time series analysis was developed for three boroughs (Santiago Centro, Cerro Navia, and El Bosque) located covering the warm period during the years 2011–2016. The number, and duration of HW and WD in each borough were determined. Daily counts of death, hospital admission, daily maximum temperature, and environmental variables were analyzed. To assess the risk of death or hospitalization for different causes and age groups during HW or WD events Generalized Additive Models were used. Results show that HW events can be localized and may not affect all areas equally. Santiago Centro had the highest tendency to record HW (16 events) and WD (152 days). The significant risk of HW-related mortality events in Santiago Centro was 2.79 [95% CI: 1.07-7.27], affecting people over 24 years old. For the three communes, the attributable risk of exposure to hot events is greater than 33.8% (mortality) and 3.9% (morbidity). This is the first approximation in the most populated Chilean city to set up robust databases to support science-based policy-making aimed at reducing health risks related to extreme weather conditions.