For a study, researchers sought to evaluate the efficacy of 2 and 3 mRNA COVID-19 vaccination doses in adults against SARS-CoV-2 Delta and Omicron disease symptoms in US outpatient settings. Between October 1, 2021, and February 12, 2022, all eligible patients with a fever, cough, or loss of taste or smell sought outpatient care or clinical SARS-CoV-2 testing within 10 days of the commencement of their illness got the research team’s approval and were included. They examined the likelihood of receiving 2 or 3 doses of the mRNA COVID-19 vaccination among SARS-CoV-2 patients compared to controls using logistic regression and the test-negative methodology. The research site, age, onset week, and past SARS-CoV-2 infection were all taken into account while changing the regression models. The formula for vaccination efficiency (VE) was (1 adjusted odds ratio)× 100%. During the Delta predominant phase, 574 (32%) of the 1,775 subjects included in the analysis tested positive for SARS-CoV-2, while 1,006 (56%) of the 1,794 subjects tested positive during the Omicron predominant phase. The VE against disease symptoms in outpatient settings where Delta predominated was 63% (95% CI: 51% to 72%) and 96% (95% CI: 93% to 98%) for mRNA patients who received 2 doses and 3 doses, respectively. When Omicron predominated, VE was 21% (95% CI: 6% to 41%) for recipients of 2 doses and 62% (95% CI: 48% to 72%) for users of 3 doses. When the Omicron variety started to be the main source of COVID-19 in the US, 3 doses of the mRNA COVID-19 vaccine provided this adult group with substantial protection against symptoms in outpatient settings. The third dosage of the mRNA COVID-19 vaccination was advised based on these findings.