<p>Dengue virus (DENV) non-structural protein NS4A and NS1 are crucial for viral replication and have the ability to cause extensive remodeling of the host cell membrane. Here, a computational strategy has been used to study the structural and functional aspects of NS4A and NS1 in membrane interaction and remodeling. By employing multiscale all atom and coarse grained molecular dynamics simulations, we investigated the conformational dynamics of NS4A and NS1 and their interactions with model lipid bilayers. Our results establish that NS4A inserts preferentially into membranes in its native state as an integral membrane protein and causes curvature aided by its oligomerization event, which is in agreement with its proposed function in replication complex formation. NS1 has stable lipid-binding domains that can anchor and induce membrane curvature or stabilize remodelled membrane structures and perform its function as a peripherally bound membrane protein. These findings give molecular-level insights into the mechanism of how DENV hijacks host membranes for replication and identify potential targets for antiviral interventions. This study also plays an important role in updating our knowledge of flaviviral manipulation of membranes.</p> Graphical Abstract <p></p>