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Calotropis gigantea, commonly known as giant milkweed, has been traditionally used for its medicinal properties, particularly in treating skin infections and inflammation. This study evaluates the antimicrobial potential of methanol and ethanol extracts from sun-dried and oven-dried leaves and flowers of C. gigantea against key human pathogens, including Propionibacterium acnes, Vibrio vulnificus, Aeromonas hydrophila, and Escherichia coli. The disc diffusion method was employed to assess antimicrobial activity, revealing that extracts from oven-dried leaves, particularly those prepared with ethanol, exhibited the strongest antimicrobial activity, notably against A. hydrophila and E. coli. Phytochemical screening of the extracts identified the presence of terpenoids, flavonoids, phenols, and sterols, compounds known for their antimicrobial and antioxidant properties. Gas chromatography-mass spectrometry (GC-MS) analysis of the ethanol extract revealed 20 bioactive compounds, with Diethyl Phthalate as the predominant compound (61.11%), alongside other compounds with potential antimicrobial and anti-inflammatory activities, such as alpha-tocopherol and 9,12,15-octadecatrienoic acid. The study highlights the efficacy of C. gigantea extracts in combating bacterial pathogens and underscores the importance of drying methods and extraction solvents in optimizing antimicrobial properties.