The high demand for wood-based composites generates a greater use of wood adhesives. The current industrial challenge is to develop modified synthetic adhesives to remove harmful formaldehyde, and to test natural adhesives. The scope of the current research included the manufacturing of high-density fiberboards (HDF) using natural binders such as polylactic acid (PLA), polycaprolactone (PCL), and thermoplastic starch (TPS) with different resination (12%, 15%, 20%). The HDF with biopolymers was compared to a reference HDF, manufactured following the example of industrial technology, with commonly used adhesives such as urea-formaldehyde (UF) resin. Different mechanical and physical properties were determined, namely modulus of rupture (MOR), modulus of elasticity (MOE), internal bonding strength (IB), thickness swelling (TS), water absorption (WA), surface water absorption (SWA), contact angle, as well as density profile; scanning electron microscope (SEM) analysis was also performed. The results showed that increasing the binder content significantly improved the mechanical properties of the panels in the case of starch binder (MOR from 31.35 N mm−2 to 40.10 N mm−2, IB from 0.24 N mm−2 to 0.39 N mm−2 for dry starch), and reduces these in the case of PLA and PCL. The wet method of starch addition improved the mechanical properties of panels; however, it negatively influenced the reaction of the panels to water (WA 90.3% for dry starch and 105.9% for wet starch after 24 h soaking). Due to dynamically evaporating solvents from the PLA and PCL binding mixtures, a development of the fibers’ resination (blending) techniques should be performed, to avoid the uneven spreading of the binder over the resinated material.