<h3>Background</h3> Targeting energy metabolism, mitochondrial, and redox homeostasis in acute leukemia can directly affect tumor progression and indirectly influence immune cells in the microenvironment. Natural products from plants have been extensively studied and shown to regulate tumor metabolism both directly and indirectly. Isolated natural products or standardized complex extracts from Petiveria alliacea, Tillandsia usneoides, Piper nigrum, and Caesalpinia spinosa exhibit cytotoxic and cytostatic activities on various tumor cell lines and antitumor activity in animal cancer models. These plant extracts alter tumor metabolism and activates the immune response. <h3><b>Method</b></h3> The purpose of our study was to identify metabolomic alterations in the endo- and exo-metabolome of K562 tumor cells treated with standardized extracts to understand the mechanisms underlying their antitumor activity. We treated K562 leukemic cell lines with inhibitory concentrations of Petiveria alliacea, Tillandsia usneoides, Piper nigrum, and Caesalpinia spinosa extracts, along with negative controls (ethanol and PBS). Cell lysates were analyzed by liquid chromatography and gas chromatography coupled with mass spectrometry in positive ionization mode. Differences between profiles were evaluated using univariate and multivariate analysis. <h3>Results</h3> Compared to the negative control, altered chemical classes of metabolites included indoles, glycerophospholipids, nucleosides, nucleotides, fatty acyls, carboxylic acids, and sphingolipids. The metabolome of treated cell lysates revealed significant alterations primarily in glycerophospholipid, purine, and biotin metabolism for P. alliacea; glutathione metabolism, the urea cycle, and phosphatidylethanolamine biosynthesis for T. usneoides; and glutamate, glutathione, alanine, and cysteine metabolism for P. nigrum and C. spinosa. Some metabolites can induce increased inflammation and pro-tumorigenic signals; for instance, we observed the downregulation of palmitic acid, which has been demonstrated to decrease immunogenicity in tumor cells. Targeting other metabolites, such as glutamine (also downregulated in our study), resulted in decreased MDSC recruitment and enhanced tumor-specific immunity. <h3>Conclusions</h3> The most impacted metabolic pathways involved metabolites such as glutamine, glycine, serine, methionine, alanine, leucine, tyrosine, and glutamate. These results underscore the importance of using standardized extracts to modulate metabolism, potentially inhibiting tumor growth and restoring antitumor immunity.