The epidermal growth-factor-like domain A (EGF-A) of the low-density lipoprotein (LDL) receptor is a promising lead for therapeutic inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). However, the clinical potential of EGF-A is limited by its suboptimal affinity for PCSK9. Here, we use phage display to identify EGF-A analogues with extended bioactive segments that have improved affinity for PCSK9. The most potent analogue, TEX-S2_03, demonstrated ∼130-fold improved affinity over the parent domain and had a reduced calcium dependency for efficient PCSK9 binding. Thermodynamic binding analysis suggests the improved affinity of TEX-S2_03 is enthalpically driven, indicating favorable interactions are formed between the extended segment of TEX-S2_03 and the PCSK9 surface. The improved affinity of TEX-S2_03 resulted in increased activity in competition binding assays and more efficient restoration of LDL receptor levels with clearance of extracellular LDL cholesterol in functional cell assays. These results confirm that TEX-S2_03 is a promising therapeutic lead for treating hypercholesterolemia. Many EGF-like domains are involved in disease-related protein-protein interactions; therefore, our strategy for engineering EGF-like domains has the potential to be broadly implemented in EGF-based drug design.