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In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid <b>1</b>, rutin <b>2</b>, gallic acid <b>3</b>, and chlorogenic acid <b>4</b> were isolated from the leaves of <i>Pimenta dioica</i> (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (<b>1</b>–<b>4</b>) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC₅₀) and SARS-CoV-2 inhibitory concentrations (IC₅₀). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with <i>P. dioca</i> aqueous extract, ferulic acid <b>1</b>, rutin <b>2</b>, gallic acid <b>3</b>, and chlorogenic acid <b>4</b> were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin <b>2</b>, gallic acid <b>3</b>, and chlorogenic acid <b>4</b> showed remarkable anti-SARS-CoV-2 activities with IC₅₀ values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid <b>1</b> and rutin <b>2</b> treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin <b>2</b> either alone or in combination with other isolates for COVID-19 management.