The growing incidence of non-communicable diseases makes the search for natural sources of bioactive compounds a priority for such disease prevention/control. Achyrocline satureioides (‘marcela’), a plant rich in polyphenols and native to Brazil, Uruguay, Paraguay, and Argentina, could be used for this purpose. Data on its antidiabetic/antiobesity properties and cellular uptake of bioactive compounds are lacking. The potentiality of non-thermal technologies such as high-hydrostatic pressure (HP) to enhance polyphenol extraction retains attention. Thus, in the present study aqueous and ethanolic marcela extracts with/without assisted-HP processing were chemically characterized and assessed for their in vitro antioxidant capacity, antidiabetic and antiobesity activities, as well as cellular cytotoxicity and uptake on intestinal cell monolayers (TC7-cells, a clone of Caco-2 cells). Aqueous and ethanolic conventional extracts presented different polyphenolic profiles characterized mainly by phenolic acids or flavonoids, respectively, as stated by reverse phase-high-performance liquid chromatography (RP-HPLC) analyses. In general, ethanolic extracts presented the strongest bioactive properties and HP had none or a negative effect on in vitro bioactivities comparing to conventional extracts. TC7-cell viability and cellular uptake demonstrated in conventional and HP-assisted extracts, highlighted the biological effects of marcela bioactive compounds on TC7-cell monolayers. TC7-cell studies showed no HP-induced cytotoxicity. In sum, marcela extracts have great potential as functional ingredients for the prevention/treatment of chronic diseases such as diabetes.