This study investigates the variations in the chemical profiles and biological activities (antioxidant and cytotoxic) of Eplingiella fruticosa from the state of Sergipe, an endemic species from the Northeast region of Brazil. The essential oils were extracted from six populations by hydrodistillation and analyzed by GC/MS-FID. Cluster analysis was performed with the data of the constituents of the essential oils, and then a dissimilarity matrix, based on Euclidean distances, and a dendrogram, through the Ward clustering method, were constructed. The antioxidant activity of the essential oils was tested by different assays (DPPH, ABTS, β-carotene, and FRAP), and cytotoxic activity was tested by the SRB assay. The compounds found in greater amounts were α-pinene, β-pinene, 1,8-cineole, camphor, borneol, δ-elemene, α-cubebene, α-ylangene, (E)-caryophyllene, germacrene D, bicyclogermacrene, trans-calamenene, spathulenol, caryophyllene oxide, and viridiflorol. These compounds defined the formation of two groups. The first group was composed of the populations of São Cristóvão, Itaporanga, Japaratuba, and Malhada dos Bois municipalities and was characterized by the presence of the monoterpene camphor (8.39-11.27%) as the compound of greatest concentration in relation to the other municipal areas. The second group was composed of the populations of Moita Bonita and Pirambu municipalities and was characterized by the major presence of the sesquiterpene bicyclogermacrene (7.45% and 10.98%). The plants exhibited weak effects in terms of antioxidant activity; however, the essential oil showed significant toxicity for the lines A549 (51.00% cell viability) in the population of Japaratuba, and B16F10 (64.94% cell viability) in Malhada dos Bois. The observations of this study may open a way to optimize the use of the E. fruticosa populations in relation to their cytotoxic properties.