This study aimed to enhance the hemocompatibility of polyethersulfone (PES) membranes by increasing their hydrophobicity. Two methods were used: chemical modification with a hydrophobic substance and creating a micropatterned structure using modified silica nanoparticles (SiO2 NP) in a mixed matrix membrane (MMM). Fibrinogen adsorption was assessed using synchrotron radiation micro-computed tomography (SR-µCT), and surface roughness was analyzed with atomic force microscopy (AFM). Hemocompatibility was evaluated by studying interactions with patients' serum and measuring the release of inflammatory biomarkers (C5a, IL-1α, IL-1β, IL-6, vWF, C5b-9 and PF-4). Differential Scanning Calorimeter (DSC) analysis determined the stability of the membrane hydration layer, and water contact angle (WCA) measurements assessed hydrophobic properties. Fourier-transform infrared spectroscopy (FTIR) and surface charge analysis examined surface stability. Molecular docking analysis showed reduced interaction between hydrophobized PES membranes and fibrinogen and albumin in human serum. SR-µCT analysis revealed 20% less fibrinogen adsorption on hydrophobized PES membrane surfaces. MMM PES membranes exhibited minimal fibrinogen adsorption due to the micropatterned structure. Both hydrophobized PES membranes demonstrated reduced vWF biomarker release (25–28%) compared to unmodified PES, with MMM PES membranes performing best. However, both hydrophobized PES membranes led to a significant increase (150%) in IL-6 upon blood contact, attributed to the reduced hydration layer. MMM PES membranes contained the least strongly bound water (0.2%) and exhibited the highest hydrophobicity (98°). This study highlights the potential of hydrophobized PES membranes and MMM structures for enhancing hemocompatibility, with opportunities for optimizing surface modifications to reduce inflammation responses while maintaining desirable properties.