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Potato chips are the most widely consumed snack in the world; therefore, they can be used as an ideal carrier for nutrient delivery. The objective of this study is to investigate the effect of impregnating vitamin E, vitamin C, and calcium through vacuum impregnation (VI) on the physico-chemical, microstructural, and starch hydrolysis (%) in vitro and estimated glycemic index (eGI) of potato chips from a variety grown in Colombia. The fortification process decreased the peak viscosity from 1428 ± 20 cP (unfortified) to 734 ± 27 cP (fortified) and increased pasting temperatures. The swelling power also decreased from 11.36 ± 0.32 g/g (unfortified) to 8.59±0.07 g/g (fortified) after the fortification. Approximately 42% and 63% of the starch is hydrolyzed in the first 10 min of small intestinal digestion for the fortified and control samples, respectively. At the end of in vitro digestion (120 min), fortified potato has 74% starch hydrolyzed, whereas the same is calculated at 95% for control samples. The microstructural characteristics of digesta obtained during in vitro digestion showed that fortified samples have well preserved cell structures. In conclusion, the addition of impregnation compounds led to a lower starch hydrolysis of potato chips with a consequent decrease in eGI.