Tailoring membrane properties for biomedical applications, e.g., hemodialysis, have been a challenge which material scientists have been addressing for last few decades. The fundamental challenge lies in identifying and controlling the parameters which are responsible for yielding cytocompatibility and hemocompatibility to the material. The present article is an attempt to understand the physical parameters which are responsible for the biological manifestations of a polymer membrane. Two types of dialysis membranes, viz., high performance membrane and high cutoff, have been synthesized. Membrane surfaces were modified via dry and wet annealing, and conditions of annealing were optimized. Subsequently, physical and surface properties of the membranes after annealing were investigated. In‐depth investigation of biological and blood response has been undertaken on the basis of fundamental parameters like polarizability and surface rigidity. Cell adhesion, proliferation, protein adsorption, hemolysis, platelet adhesion, thrombus formation, and complement activation tests were performed on the membranes. It was observed that dry heating increases surface smoothness but in the process develops cracks on membrane surface as well as increases work of adhesion for blood contact. On the other hand, wet heating of membrane surface not only improves biological performance but it is also easy to retrofit with existing spinning technologies for spinning dialysis membranes. In‐house spinning technology was used to synthesize hemodialysis membranes which were annealed at the optimized conditions, and their surfaces were compared with commercial fibers to ascertain the rationale of annealing as a facile method to lend desired surface properties to membranes. Copyright © 2016 John Wiley & Sons, Ltd.