Fatigue, characterized by periods of exhaustion that interfere with normal activities and negatively affect quality of life, can be classified as prolonged fatigue (or short-term fatigue, SF) or chronic fatigue. Vitamin deficiency and chronic inflammation seem to be possible causes of fatigue. Due to the unavailability of effective remedies that attenuate fatigue and provide consumer satisfaction, the aim of this investigation is to assess whether a commercial food supplement consisting of pomegranate extract with known anti-inflammatory activity, B vitamins, and vitamin C can help fight SF. To this end, the chemical composition of whole fruit pomegranate dry extract was determined through a RP-UHPLC–HRMS method, which indicated the presence of ellagitannins, gallotannins, and organic and phenolic acids. In a survey of consumers of food supplements aimed at reducing fatigue, 78 subjects (21 men and 57 women) were recruited for one month to evaluate the efficacy and tolerability of this food supplement through validated questionnaires for assessing fatigue level and quality of life. The consumers reported a significant improvement in their conditions without adverse effects over this time period. Although further studies are needed, these preliminary data suggest the capacity of a combination of pomegranate extract and hydrosoluble vitamins to alleviate SF.