A two-level full factorial design 22 with three replications was employed to assess the effect of the incorporation of PSF into the epoxy matrix and the surface treatment of carbon fibers on the work of adhesion (WA) and the interfacial shear strength (IFSS) of carbon fiber–epoxy composites. The IFSS was determined using the microbond (or microdrop) micromechanical test, and the work of adhesion was estimated using two different procedures: (1) using the Owens and Wendt method, and (2) from the Dupre–Young expression using the contact angle θ of a cured epoxy resin on a single carbon fiber and the surface energy of the cured epoxy resin. It was found that the treatment of the carbon fiber with the silane-coupling agent appreciably increases its polar component because of the nitric acid oxidation and the chemisorption of the silane-coupling agent onto the carbon fiber surface. Also, the O=S=O group present in the polysulfone chain resin fairly increases the polar component of the epoxy–PSF blend. The results show that the wetting of the silane-treated carbon fiber by the thermoplastic-modified epoxy resin is better, thus increasing the fiber–matrix adhesion. It was also found that there is a similarity between the trends of both, the IFSS and the WA results. Also, from the ANOVA results it was also seen that both the incorporation of the PSF to the epoxy matrix and the surface treatment of the carbon fibers and their interaction were statistically significant to the IFSS and the WA.