Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic of the multisystem disease coronavirus disease-2019 (COVID-19). Since the development of COVID-19 vaccines, there has been extensive monitoring for potential serious side effects. We report an unusual presentation of acute deep vein thrombosis (DVT) in the right upper extremity of a 27-year-old Caucasian female, 3 days after receipt of her second dose of the Moderna COVID-19 vaccine. Her relevant thrombophilia workup was negative on initial presentation. She was treated with rivaroxaban for 3 months and her symptoms of right upper extremity swelling, and pain improved. Considering our case did not have any evidence of thrombocytopenia, we discuss the possible pathophysiology of acute DVT following Moderna COVID-19 vaccine in contrast to adenoviral vector COVID-19 vaccines (ChAdOx1 nCoV-19 and Ad26. COV2. S), including mRNA COVID-19 vaccine binding to pattern recognition receptors (PRR) in the endosomes and cytosol leading to a pro inflammatory cascade and coagulopathy. We highlight the importance of initial workup for acute DVT post COVID-19 vaccination, that should include complete blood count (CBC) with platelet count, international normalized ratio (INR), prothrombin time (PTT), D-dimer levels, fibrinogen levels, platelet factor 4 (PF4)/heparin enzyme-linked immunosorbent assays (ELISA) followed by a confirmatory PF4 platelet activation assay such as serotonin release assay, P-selectin expression assay, or heparin induced platelet aggregation (HIPA) assay, and imaging for thrombosis.