The aim of this study was to evaluate the effect of the type of protein used on the in vitro content and bioavailability of polyphenolic compounds from microcapsules with a cranberry polyphenolic core (CF). The effect of the carriers on the physicochemical properties of the microcapsules, swelling capacity in specific sections of the gastrointestinal tract, and safety of use was also examined by assessing biocompatibility with normal colonic epithelial cells. The microcapsules were prepared by ionotropic gelation using seven matrices: alginate (AL) and AL with whey protein isolate (WPI), pea protein isolate (PPI), soybean protein isolate (SPI), pumpkin protein isolate (PNPI), sunflower protein isolate (SNPI), and rice protein isolate (RPI). According to the results, all microcapsules demonstrated comparable and satisfactory properties in terms of dry weight, diameter, hygroscopicity, color, and biocompatibility. However, the choice of protein significantly influenced the values of other parameters. Microcapsules based on SPI provided the best process efficiency, while higher polyphenol content and antioxidant activity were observed for microcapsules containing SNPI and PNPI. In contrast, the highest bioavailability was estimated for microcapsules containing WPI. These findings could have significant implications for the design of new formulations and products for the food, nutraceutical, and pharmaceutical industries.