In February 2021, a cluster of Beta variant (B.1.351) coronavirus disease 2019 (COVID-19) cases were identified in an apartment building located in Northern Ontario, Canada. Most cases had no known contact with each other. Objectives of this multi-component outbreak investigation were to better understand the social and environmental factors that facilitated the transmission of COVID-19 through this multi-unit residential building (MURB). A case–control study examined building-specific exposures and resident behaviours that may have increased the odds of being a case. A professional engineer assessed the building’s heating, ventilation, and air-conditioning (HVAC) systems. Whole-genome sequencing and an in-depth genomic analysis were performed. Forty-five outbreak-confirmed cases were identified. From the case–control study, being on the upper floors (OR: 10.4; 95% CI: 1.63–66.9) and within three adjacent vertical lines (OR: 28.3; 3.57–225) were both significantly associated with being a case of COVID-19, after adjusting for age. There were no significant differences in reported behaviours, use of shared spaces, or precautions taken between cases and controls. An assessment of the building’s ventilation found uncontrolled air leakage between apartment units. A single genomic cluster was identified, where most sequences were identical to one another. Findings from the multiple components of this investigation are suggestive of aerosol transmission between units.