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Objective: Methicillin-resistant Staphylococcus aureus (MRSA) strains are a leading cause of communicable disease in community and nosocomial settings. They are responsible for high morbidity and mortality. Researchers currently pursue novel antimicrobials from natural sources against non-traditional drug targets of staphylococci to ensure a pipeline of potent drugs, in the face of rising drug resistance. The focus of this study was to screen compounds from a freshwater isolate of Chlorella sorokiniana for anti-staphylococcal activity, using traditional microbiology, phytochemical analysis and bioinformatics approaches. Methods: Chlorella sorokiniana methanol extract was investigated for its antimicrobial potential on Staphylococcus aureus strains (ATCC and MRSA isolates) by Kirby Bauer disc diffusion, broth microdilution, cell cytotoxicity and thin layer chromatography-bioautography (TLC-BA). Two antimicrobial TLC-BA antimicrobial fractions (A and B) were subject to gas chromatography mass spectrometry (GCMS). The structures of 9 compounds representing GCMS peaks were tested in silico, for their pharmacokinetic properties and binding energy efficiency with the target, using Molinspiration tool and Autodock 4.2. Results: Mean zone diameter of inhibition of growth by CSME (20 mg) was 21 mm, MIC/MBC was 0.31/2.5 mg/L. GCMS analysis of TLC fraction-A revealed 31 phytochemicals, of which 2-pentanone,4-hydroxy-4-methyl- had the highest area % (65.61) and TLC fraction-B revealed 4 peaks of which pentadecanoic acid and 1-(+)-ascorbic acid 2,6-dihexadecanoate had the highest area % (45.57, 48.09).In silico analysis of 9 peak compounds on the target of interest showed that compound 2: 2-pentanone,4-hydroxy-4-methyl- and compound 7: 1,2 – benzene dicarboxylic acid, mono (2- ethylhexyl) ester, satisfied Lipinski’s rule of 5, and displayed the least binding energies −6.93 and −5.74 with ClpP protease, thus holding pharmaceutical potential, and supporting further investment into in vitro and in vivo studies. Conclusions: C. sorokiniana, a less studied microalga thus offers a promising natural resource for anti-MRSA phytochemicals, capable of targeting ClpP1 protease.(290 words)