Food-drug interactions (FDIs) arise when nutritional dietary consumption regulates biochemical mechanisms involved in drug metabolism. Towards characterizing the nature of food’s influence on pharmacological treatment, it is essential to detect all possible FDIs. In this study, we propose FDMine, a novel systematic framework that models the FDI problem as a homogenous graph. In this graph, all nodes representing drug, food and food composition are referenced as chemical structures. This homogenous representation enables us to take advantage of reported drug-drug interactions for accuracy evaluation, especially when accessible ground truth for FDIs is lacking. Our dataset consists of 788 unique approved small molecule drugs with metabolism-related drug-drug interactions (DDIs) and 320 unique food items, composed of 563 unique compounds with 179 health effects. The potential number of interactions is 87,192 and 92,143 when two different versions of the graph referred to as disjoint and joint graphs are considered, respectively. We defined several similarity subnetworks comprising food-drug similarity (FDS), drug-drug similarity (DDS), and food-food similarity (FFS) networks, based on similarity profiles. A unique part of the graph is the encoding of the food composition as a set of nodes and calculating a content contribution score to re-weight the similarity links. To predict new FDI links, we applied the path category-based (path length 2 and 3) and neighborhood-based similarity-based link prediction algorithms. We calculated the [email protected] (top 1%, 2%, and 5%) of the newly predicted links, the area under the receiver operating characteristic curve, and precision-recall curve. We have performed three types of evaluations to benchmark results using different types of interactions. The shortest path-based method has achieved a precision 84%, 60% and 40% for the top 1%, 2% and 5% of FDIs identified, respectively. We validated the top FDIs predicted using FDMine to demonstrate its applicability and we relate therapeutic anti-inflammatory effects of food items informed by FDIs. We hypothesize that the proposed framework can be used to gain new insights on FDIs. FDMine is publicly available to support clinicians and researchers.