Pleuropericardial syndrome, a rare inflammatory complication associated with messenger ribonucleic acid (mRNA) COVID-19 vaccination, is predominantly reported in younger men but may also occur in older adults following booster doses, as illustrated by this case of a 68-year-old woman. Three days after receiving her third (booster) dose, she presented with flu-like symptoms, palpitations, and progressively worsening dyspnea. Diagnostic imaging revealed a large pericardial effusion and a moderate pleural effusion. Emergent pericardiocentesis was performed, draining 850 mL of serosanguinous fluid. Subsequent anti-inflammatory therapy led to complete resolution of symptoms, with no recurrence over a 15-month follow-up period. This presentation is likely driven by immune-mediated serosal inflammation, potentially triggered by the activation of innate immune pathways or molecular mimicry following mRNA vaccination. This case underscores the importance of prompt recognition and thorough differential diagnosis, even in atypical patient demographics such as older women postbooster vaccination. It further highlights the need for systematic reporting of such adverse events to pharmacovigilance systems, thereby supporting ongoing vaccine safety monitoring and informing future booster strategies.