As COVID-19 vaccines gain more prevalence, previously unrecognized side effects continue to be reported. We report a case of 78 male with no significant past medical history who was found to have a unilateral pleural effusion with symptoms that started two days after the administration of a COVID-19 vaccine. The initial presumption was bacterial pneumonia with parapneumonic effusion. However, the lack of clinical response prompted surgical intervention, and a diagnosis of empyema was established. No evidence of infectious etiology was found. This case helps to support the previously limited evidence in the recent medical literature that suggests a possible association between COVID-19 vaccines and pleurisy/effusion.