The analysis and quantification of plant metabolites is a major challenge as medicinal and aromatic plant extracts are very complex and there is a lack of commercially pure standards that are important for both identification and quantification. The aim of this work is to compare the performance of different detectors (PDA and MS) used in high performance liquid chromatography and acquisition modes (Selected Ion Monitoring (SIM) and Selected Reaction Monitoring (SRM) in MS) for the quantification of specialized plant metabolites (i.e. phenolic and triterpenic compounds). All metabolites were quantified using the above detection methods with the reference standard and with a compound with similar UV and MS spectra (semi-quantification) to simulate the very common cases where the reference standard is not available or accessible. The precision of each quantification approach was evaluated by the percentage relative error based on the actual concentration of the quantified compound. The quantification precision was also tested in the presence of interferences and in two case studies, i.e. leaf extracts of Cynara cardunculus subsp. cardunculus L. and Punica granatum L.. The results show that quantification with the reference standard is certainly more precise. For semi-quantification, SIM and especially SRM are less suitable as they are more selective compared to PDA, but they allow detection and approximate quantification of the molecule of interest limiting interference, especially in complex matrices where coelution is sometimes unavoidable. A correction method is also proposed to overcome the over-underestimation that can occur with semi-quantification.