Many countries reported an increase of out-of-hospital cardiac arrests (OHCAs) and mortality during the COVID-19 pandemic. However, all these data refer to regional settings and national data are still missing. We aimed to assess the OHCA incidence and population mortality during COVID-19 pandemic in whole Switzerland and in the different regions (Cantons) according to the infection rate. We considered OHCAs and deaths which occurred in Switzerland after the first diagnosed case of COVID-19 (February 25th) and for the subsequent 65 days and in the same period in 2019. We also compared Cantons with high versus low COVID-19 incidence. A 2.4% reduction in OHCA cases was observed in Switzerland. The reduction was particularly high (−21.4%) in high-incidence COVID-19 cantons, whilst OHCAs increased by 7.7% in low-incidence COVID-19 cantons. Mortality increased by 8.6% in the entire nation: a 27.8% increase in high-incidence cantons and a slight decrease (−0.7%) in low-incidence cantons was observed. The OHCA occurred more frequently at home, CPR and AED use by bystander were less frequent during the pandemic. Conversely, the OHCAs percentage in which a first responder was present, initiated the CPR and used an AED, increased. The outcome of patients in COVID-19 high-incidence cantons was worse compared to low-incidence cantons. During the COVID-19 pandemic in Switzerland mortality increased in Cantons with high-incidence of infection, whilst not in the low-incidence ones. OHCA occurrence followed an opposite trend showing how variables related to the health-system and EMS organization deeply influence OHCA occurrence during a pandemic.