<i>Ganoderma</i> species have been used in folk medicine against different illnesses and are characterized by producing a diversity of bioactive metabolites (triterpenoids, polysaccharides, flavonoids, and phenols) with numerous medicinal effects (anti-proliferative, antioxidant, anti-inflammatory, and antibacterial). This work aims to evaluate ethanolic extracts of fruiting bodies of <i>Ganoderma oerstedii, G. weberianum</i>, and <i>G. subincrustatum</i> strains from the Sonoran Desert in the anti-proliferative activity by the MTT assay on cancer cell lines; anti-inflammatory effect by quantifying nitric oxide (NO) production; antioxidant activity by DPPH, ABTS, and FRAP assays; total phenolic and flavonoid content by Folin-Ciocalteu and AlCl<sub>3</sub> method, respectively; antibacterial activity by the broth microdilution method against <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>. Extracts showed anti-proliferative activity with IC<sub>50</sub> < 100 µg/mL on the cancer cell lines MDA-MB-231, A549, and HeLa, except <i>G. subincrustatum</i> extract with an IC<sub>50</sub> > 100 µg/mL; anti-proliferative activity was not selective, being affected non-cancerous cell line ARPE-19. Extracts showed significant inhibition of NO release in cells stimulated by LPS, up to 60% with <i>G. subincrustatum</i> and <i>G. oerstedii</i>, and 47% with <i>G. weberianum</i>. All tested assays showed moderate antioxidant potential; the most active was <i>G. lucium</i> (control strain) with IC<sub>50</sub> of 69 and 30 µg/mL by DPPH and ABTS respectively; and 271 µg Trolox equivalents/g by FRAP. Total phenols and flavonoids ranged from 38 to 56 mg GAE/g and 0.53 to 0.93 mg QE/g, respectively. A significant correlation was found between the antioxidant activities revealed by DPPH, ABTS, and FRAP with total phenol and flavonoid contents. Antibacterial activity was weak against <i>S. aureus</i> (MIC<sub>50</sub> > 10 mg/mL). These results demonstrate that tested <i>Ganoderma</i> mushrooms have medicinal potential such as anti-inflammatory and anti-proliferative.