In this work, a systematic comprehensive screening procedure has been proposed for the detection of multiclass flavonoid derivatives by liquid chromatography high-resolution mass spectrometry (LC-HRMS). The procedure is based on the combined use of accurate mass measurements and in-source fragmentation obtained with a liquid chromatography time-of-flight mass spectrometry instrument. The method relies on automated screening of selected diagnostic ions based on an exact mass database. The included diagnostic ions represent theoretical combinations of aglycones and typical glycan part constituents of flavonoid derivatives (i.e., various saccharide units and acyl moieties). The proposed identification protocol is following a systematic evaluation of the obtained positive hits from the diagnostic ions database according to a "bottom-up" approach that is thoroughly discussed. The main benefit of the proposed bottom-up protocol resides in the fact that untargeted flavonoid derivatives can be detected and tentatively identified without the need for any preliminary knowledge on the sought compound. In addition to information on the nature of the (1) aglycone and the (2) glycan part, further indication of (3) sugar unit distribution and information on (4) the type of the glycosidic bonds can also be attained. Selected examples of plant extracts demonstrate the potential of the proposed LC-HRMS approach for the systematic screening of flavonoids. A broad variety of compounds were tentatively identified including both anthocyanins and non-anthocyanin flavonoids having various glycan moieties such as mono-, di-, and triglycosides with varying distributions and linkage types of carbohydrate moieties (O-glycosides, C-glycosides, O,C-glycosides).