The cardiovascular disease (CVD) protection by almonds is well-established. Where most clinical studies used high dose almonds with food, some recent indications suggest almonds′ use as snacks (without accompanying foods). Pharmacological effects of multiple almond-doses, given with or without food had not been explored. In animal models, we simultaneously compared the effect of food on medicinal properties of multiple almond-doses. Study-1 (tyloxapol model) determined the minimum effective dose in rats. Group 1-2 received normal diet (ND). Groups 3-8 received 1, 3 and 10 g/kg-1 American and Pakistani almond varieties. After four weeks, tyloxapol was injected to all groups except group 1 which received saline. Study-2 and study-3, on American and Pakistani almonds respectively, explored the effect of food on almonds′ efficacy, in high-fat diet (HFD) rat model. Group-1 received ND and all other groups received HFD. For four weeks almonds (doses 0.5, 1, and 2 g/kg-1) were given with and without food, to groups 3-8, after which blood was drawn. Almonds inhibited hyperlipidemia, hyperurecemia, hyperphosphatemia, increase in serum alkaline phosphatase, gamma-glutamyl transferase, aspartate and alanine aminotransferase. With food, anti-hyperlipidemia was at 3 and 10 g/kg-1, in tyloxapol model; and 2 g/kg-1 in HFD model. Low dose (1 g/kg-1), ineffective when given with food, significantly prevented hyperlipidemia, hepatic and vascular dysfunction when coupled with two-hour fasting. In conclusion, medicinal value of almond can be maximized by consuming low doses in empty stomach. This study impacts the cost associated with life-long use of nuts for preventing chronic disorders like CVDs.