In this study we focused on four taxa of the genus Calendula (C. maritima, C. suffruticosa subsp. fulgida, C. arvensis, and the hybrid between the first two ones), collected in Mediterranean area (Sicily). Six extracts for each species were obtained using solvents with increasing polarity (hexane, ethanol 80%, acetone 70%, and water) and through extraction by supercritical fluids (SFE). It has been observed that the solvent with the highest extraction efficiency was ethanol 80% for all species. However, SFE extracts showed high antioxidant activity comparable to the ethanol 80% extract (polyphenol, DPPH, and reducing power method). These findings were confirmed by in vitro analysis (MTT assay) where it was observed that the tested concentration (24 µg/mL), obtained from ethanol 80% and SFE extracts, showed a protective effect comparable to that induced by a synthetic antioxidant. Extraction with SFE ensured a great selectivity by avoiding the use of toxic organic solvents and thus consisted of a promising technique for sustainable production of Calendula extracts.