Objective: Describe a SARS-CoV-2 hospital outbreak and the role of serial testing of patients and healthcare personnel (HCP) in interrupting transmission. Design: Outbreak investigation Setting: Medical floor of a tertiary care center in Minnesota Methods: Serial testing for SARS-CoV-2 and whole genome sequencing (WGS) of positive specimens from HCP and patients was used. An outbreak-associated case was defined as a positive SARS-CoV-2 molecular test in HCP who worked on the floor prior to testing positive or in a patient who was hospitalized on the medical floor during October 27–December 1, 2020. WGS was used to understand potential routes of transmission. Results: The outbreak was detected after a patient hospitalized for 12 days tested positive for SARS-CoV-2. Serial testing of patients and HCP was conducted in response. Overall, 247 HCP and 41 patients participated in serial SARS-CoV-2 testing. Fifty-two (21%) HCP and 19 (46%) hospitalized patients tested positive. One additional HCP tested positive outside of serial testing. WGS of specimens from 27 (51%) HCP and 15 (79%) patients identified three distinct transmission clusters. WGS and epidemiologic evidence suggested intrafacility transmission. The proportion of asymptomatic and pre-symptomatic patients who tested positive (63%) and HCP who worked during their infectious period (75%) highlight the need for serial testing of asymptomatic patients and HCP during outbreaks. Conclusions: Coupled with preventive measures such as personal protective equipment use and physical distancing, serial testing of HCP and patients could help detect and prevent transmission within healthcare facilities during outbreaks and when nosocomial transmission is suspected.