Secondary metabolites are an almost unlimited reservoir of potential bioactive compounds. In view ofthe wide chemical space covered by natural compounds, their comprehensive analysis requires multiplecutting-edge approaches. This study evaluates the applicability of ultra-high performance supercriti-cal fluid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UHPSFC-QqToF-MS)as an analytical strategy for plant metabolites profiling. Versatility of this analytical platform was firstassessed using 120 highly diverse natural compounds (according to lipophilicity, hydrogen bond capa-bility, acid-base properties, molecular mass and chemical structure) that were screened on a set of 15rationally chosen stationary phase chemistries. UHPSFC-QqToF-MS provides a suitable analytical solu-tion for 88% of the tested compounds. Three stationary phases (Diol, not endcapped C18 and 2-EP) werehighlighted as particularly polyvalent, since they allow suitable elution of 101 out of 120 natural com-pounds. The systematic evaluation of retention and selectivity of natural compounds further underlinedthe suitability of these three columns for the separation of natural compounds. This reduced set of key sta-tionary phases constitutes a basis for untargeted scouting analysis and method development. Even if theywere less versatile, stationary phases such as endcapped T3C18, polar P-PFP, were nevertheless foundto provide extended selectivity for specific natural molecules sub-classes. Finally, the identified polyva-lent conditions were successfully applied for the analysis of complex polar and non-polar plant extracts.These first experimental hits demonstrate the full applicability and potential of UHPSFC-QqToF-MS forplant metabolite profiling.