The present study reports on the development of binary blends consisting of bio-based high-density polyethylene (bio-HDPE) with polylactide (PLA), in the 5−20 wt% range, prepared by melt compounding and then shaped into pieces by injection molding. In order to enhance the miscibility between the green polyolefin and the biopolyester, different reactive compatibilizers were added during the melt blending process, namely polyethylene-grafted maleic anhydride (PE-g-MA), poly(ethylene-coglycidyl methacrylate) (PE-co-GMA), maleinized linseed oil (MLO), and a combination of MLO with dicumyl peroxide (DCP). Among the tested compatibilizers, the dual addition of MLO and DCP provided the binary blend pieces with the most balanced mechanical performance in terms of rigidity and impact strength as well as the highest thermal stability. The fracture surface of the binary blend piece processed with MLO and DCP revealed the formation of a continuous structure in which the dispersed PLA phase was nearly no discerned in the bio-HDPE matrix. The resultant miscibility improvement was ascribed to both the high solubility and plasticizing effect of MLO on the PLA phase as well as the cross-linking effect of DCP on both biopolymers. The latter effect was particularly related to the formation of macroradicals of each biopolymer that, thereafter, led to the in situ formation of bio-HDPE-co-PLA copolymers and also to the development of a partially cross-linked network in the binary blend. As a result, cost-effective and fully bio-based polymer pieces with improved mechanical strength, high toughness, and enhanced thermal resistance were obtained.