High-molecular-weight hypromellose (HPMC) and hydroxypropyl cellulose (HPC) are widely known, extended-release polymers. Conventional high-molecular-weight HPMCs are preferred in extended-release applications but not widely used in twin-screw melt granulation due to processability difficulties at low operating temperatures and potential drug degradation if high processing temperatures are used. Conversely, high-molecular-weight grade HPC (Klucel®) can be used in melt granulation processes. The purpose of this study was to evaluate the processability and dissolution behavior of HPC GXF ((Klucel® GXF) and a recently introduced type of hot-melt extrudable HPMC (Affinisol®) in extended-release metformin hydrochloride formulations using twin-screw melt granulation. Powder blends were prepared with 75% w/w metformin HCl and 25% w/w polymeric binder. Blends were granulated at processing temperatures of 160, 140, 120 and 100 °C. HPMC HME 4M (Affinisol® 4M) provided a fine powder, indicating minimum granulation at processing temperatures lower than 160 °C, and the tablets obtained with these granules capped during tableting. In contrast, acceptable tablets could be obtained with HPC GXF at all processing temperatures. Rheological studies including capillary rheometry to measure steady shear rate viscosity, and rotational rheometry to obtain time and temperature superposition data, showed that HPC GXF had a greater thermoplasticity than HPMC HME 4M, which made granulation possible with HPC GXF at low temperatures. Tablets compressed with granules obtained at 160 °C with both binders showed comparable dissolution profiles. High-molecular-weight HPC GXF provided a better processability at low temperatures and adequate tablet strength for the melt granulation of metformin HCl.