Amorphous solid dispersion (ASD) is one of the promising formulations to improve oral bioavailability of poorly water soluble drugs. However, the incomplete understanding of physical chemistry of ASD and the relation of material science to processability and pharmaceutical performance is the main setback behind the limited commercial success of ASD. The current work attempts to identify an interplay of the physicochemistry of the selected active pharmaceutical ingredients (APIs) and relevant polymers with the different underlying manufacturing processes to yield ASD of desired quality attributes. Fenofibrate and carvedilol were selected as model poorly water soluble APIs while HPMC, PVPVA 64, Eudragit E and Soluplus® were hydrophilic polymeric carriers. Solid dispersions with different drug loadings were prepared by hot melt extrusion (HME) and spray drying (SD). The extrudates resulting from HME were subsequently cryo-milled. The solid-state properties such as miscibility, crystallinity and API-carrier interactions were characterized using modulated DSC, pXRD, FTIR spectroscopy. Furthermore, physical stability was accessed following exposure to elevated temperature and humidity and in vitro dissolution behavior of ASD were studied in aqueous medium. Comparison of the drug-polymer miscibility and intermolecular interactions of ASD prepared by HME with that prepared by SD were made. The initial-physical states were related with the physical stability and in vitro dissolution behaviour. Moreover, the extent of impact of processing methods of the resulting physical structure of ASD was associated with the physicochemical properties of APIs as well as polymers. The physical states of formulation and process interplays eventually led to the diverse extent and rates of in vitro drug dissolution kinetics as well as the physical stability behaviours under the stressed conditions.