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Salvia clandestina L. is a wild perennial species present in the Salento area of Italy. Here, we examined the in vitro effects of an aqueous extract of S. clandestina L. on the MG‐63 osteosarcoma cell line. The extract reduced osteosarcoma cell viability mainly by way of apoptosis, as we observed (1) upregulation of gene and protein expression of p53, cyclin‐dependent kinase inhibitors p21WAF1 and p27Kip1, and proapoptotic BAX; (2) activation of caspases; and (3) induction of a sub‐G1 peak in the cell cycle. The mitogen‐activated protein kinases (MAPKs) JNK1/2 and p38 are activated and involved in the intracellular effects of the S. clandestina extract, as preincubation with the JNK1/2 inhibitor SP600125 or the p38 inhibitor SB203580 significantly decreased S. clandestina extract–induced cytotoxicity and inhibited increase in p53, p21WAF1, p27Kip1, and BAX. SP600125 also inhibited mRNA levels for all the aforementioned proteins, while SB203580 only affected p53 mRNA. Furthermore, S. clandestina extract treatment counteracted epithelial‐to‐mesenchymal transition, inhibited cell migration, and decreased the expression and activity of matrix metalloproteinase MMP2. In addition, S. clandestina extract enhanced the cytotoxic activity of cisplatin on MG‐63 cells through downregulation of the Akt/PKB protein kinase. We conclude that S. clandestina extract may be a novel agent for osteosarcoma treatment., In this report, we examined the effects of an aqueous extract of Salvia clandestina L. on the MG‐63 osteosarcoma cell line. The extract reduced osteosarcoma cell viability mainly by inducing apoptosis; it also counteracted epithelial‐to‐mesenchymal transition, inhibited cell migration, and decreased the expression and activity of matrix metalloproteinase MMP2, as well as enhanced the cytotoxic activity of cisplatin. S. clandestina extract may therefore be a novel agent for osteosarcoma treatment.