Objective: To study the chemical profile, antimicrobial properties, and synergistic effect with known antibiotics of essential oil extracted from the marine red macroalgae Centroceras clavulatum (C. Agardh) Montagne, collected in Morocco. Methods: The chemical composition of the oil was analyzed by gas chromatography-mass spectrometry. The oil was evaluated for antibacterial (Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus, and Klebsiella pneumoniae), and antifungal activity (Candida albicans, Candida glabrata, Candida krusei, and Candida parapsilosis), by the disc diffusion method. The minimum inhibitory and minimum microbicidal concentrations of the oil were determined, as well as the synergistic effects of its application combined with the antibiotics ciprofloxacin and fluconazole, by the checkerboard method. Results: Thirty molecules were identified in the essential oil, comprising 96.27% of the total oil composition. Monoterpenes such as carvacrol (36.06%) were the most abundant compounds, followed by caryophyllene (14.67%), endo-borneol (9.04%), pyroterebic acid (3.23%) and caryophyllene oxide (3.13%). The oil exhibited a moderate antimicrobial activity with inhibition zone diameters ranging from 9.0 to 15.0 mm. The minimum inhibitory concentration values varied between 0.9 and 14.7 mg/mL, and Bacillus subtilis and Escherichia coli were the more sensitive bacteria with 0.9 and 1.9 mg/mL, respectively. The minimum microbicidal concentration values ranged from 0.4 to 14.7 mg/mL. A significant synergic action was observed when the oil was applied in combination with ciprofloxacin and fluconazole, with fractional inhibitory concentration index values ranging from 0.31 to 0.50. Synergy was found in 80% of the combinations and a 2 to 16-fold reduction of antibiotics MIC was observed. Conclusions: Our findings suggest that the essential oil of Centroceras clavulatum should be further appraised for its potential use in the management of multi-drug resistant microorganisms, with the purpose to restore the activity of standard antimicrobial drugs.