This research focuses on the development and optimization of polymer-lipid hybrid nanoparticles (PLHNs) using two grades of mPEG-PCL co-polymers in combination with DPPC and lecithin to address the biopharmaceutical challenges of acalabrutinib (ACP), a selective treatment for different hematological malignancies. : Variations in the mPEG-to-ε-caprolactone ratio influenced both the molecular weight (Mw) of the synthesized co-polymers and their aqueous phase affinity. The ACP-loaded PLHNs (ACP-PLHNs) were optimized using a circumscribed central composite design. The in vivo studies were performed in Wistar rats. : The lipophilic mPEG-PCL (Mw = 9817.67 Da) resulted in PLHNs with a particle size of 155.91 nm and 40.08% drug loading, while the hydrophilic mPEG-PCL (Mw = 23,615.84 Da) yielded PLHNs with a relatively larger size (223.46 nm) and relatively higher drug loading (46.59%). The drug release profiles were polymer-grade dependent: lipophilic ACP-PLHNs (ACP-PLHNs) sustained release up to 30 h in pH 7.2 buffer, while hydrophilic ACP-PLHNs (ACP-PLHNs) completed release within 24 h. Stability studies showed greater stability for ACP-PLHNs, likely due to reduced molecular rearrangement from the chemically stable lipophilic co-polymer. : Oral administration of both formulations exhibited a 2-fold ( < 0.001) improvement in the C and AUC and a 3.9-fold ( < 0.001) increase in the relatively oral bioavailability compared to the conventional ACP suspension in male wistar rats.