<p>Hemostasis is a sophisticated physiological process that regulates bleeding and plays a pivotal role in wound healing and surgical interventions. Current commercial hemostatic agents exhibit limitations in terms of hemostatic efficacy, biodegradability, immunogenic responses, customization, and patient experience, potentially delaying the wound healing process. Therefore, the development of efficient, customizable hemostatic scaffolds with optimized surface properties is imperative for enhanced wound healing and regulation of hemostasis. Cellulose has emerged as a promising candidate for hemostatic applications because of its inherent biocompatibility and tunable physicochemical properties. However, the correlation between surface characteristics and structural integrity of cellulose-based scaffolds, along with their biochemical responses, remains inadequately understood. This review critically analyzes the influence of interface and surface properties of cellulose scaffolds on hemostatic modulation. We systematically examine the hemostatic cascade and its challenges in synthetic biomaterial systems, followed by an analysis of various cellulose sources and fabrication methodologies that influence scaffold properties. This review emphasizes the interface-dependent characteristics of cellulose scaffolds, particularly focusing on how chemical composition, surface topography, porosity, and mechanical properties influence blood-material interactions and subsequent clot formation. Additionally, we evaluate various surface modification strategies to enhance hemostatic efficacy. We hope that this comprehensive analysis will provide insights into optimizing surface and interface properties of cellulose scaffolds for improved hemostatic applications.</p> Graphical abstract <p>This image has been created using the Creative Common Biorender software (https://www.biorender.com/).</p>