Aims:  To evaluate the antibacterial and free‐radical scavenging (FRS) activities of propolis collected from three different areas of Sonoran Desert in northwestern Mexico [Pueblo de Alamos (PAP), Ures (UP) and Caborca (CP)]. Methods and Results:  The antibacterial and FRS activities of Sonoran propolis were determined by the broth microdilution method and the DPPH (1,1‐diphenyl‐2‐picrylhydracyl) assay, respectively. Propolis samples had antibacterial activity against only Gram‐positive bacteria. The UP sample showed the highest antibacterial activity against Staphylococcus aureus [minimal inhibitory concentration (MIC) 100 μg ml−1] in a concentration‐dependent manner (UP > CP > PAP). Caffeic acid phenethyl ester (CAPE), a UP propolis constituent, had very high growth‐inhibitory activity towards Gram‐positive bacteria, particularly against S. aureus (MIC 0·1 mmol l−1). To our knowledge, this is the first study showing a strong antibacterial activity of CAPE against S. aureus. Additionally, propolis CP exhibited high FRS activity (86% ± 0·3 at 100 μg ml−1) comparable with those of the reference antioxidants vitamin C (87·4% ± 1·7 at 70 μmol l−1) and BHT (66·07% ± 0·76 at 140 μmol l−1). The propolis compounds CAPE and rutin showed high FRS activity (90·4% ± 0·2 and 88·5% ± 0·8 at 70 μmol l−1, respectively). Conclusions:  Sonoran propolis UP and CAPE had strong antibacterial activity against S. aureus. In addition, propolis CP showed potent FRS activity comparable with those of vitamin C and BHT. Significance and Impact of the study:  The strong antibacterial and antioxidant properties of Sonoran propolis and some of its constituents support further studies on the clinical applications of this natural bee product against S. aureus and several oxidative damage‐related diseases.