The effect of main ingredients (wheat flours, polyol sweeteners, and frying oil) and infrared-assisted deep-frying on the acrylamide, 5-hydroxymethylfurfural (HMF), oil content, and physicochemical characteristics of fried dough twist (FDT) were investigated. The amount of acrylamide and HMF produced in FDT made with low-gluten flour is significantly lower than that of flour with high gluten content. Among polyol sweeteners, maltitol causes the greatest reduction in acrylamide and HMF in FDT. Moreover, the oil content of FDT was significantly reduced by optimizing the infrared-assisted deep-frying process. At last, compared with deep-frying FDT made of sucrose, infrared-assisted deep-frying FDT made of maltitol reduced acrylamide, HMF, and oil content by 61.8%, 63.4%, and 27.5%, respectively. This study clearly showed that the ingredients, flour and polyol sweeteners used to process FDT are the two major determinants of the formation of acrylamide and HMF in FDT, and infrared-assisted deep-frying can significantly affect the oil content in FDT. Simultaneously, the mitigation of the acrylamide, HMF, and oil content in FDT can be achieved by using low-gluten flour and maltitol in the ingredients, combined with infrared-assisted deep-frying.