Genus of the Zygophyllaceae family includes evergreen shrub species. Background highlights the antioxidant and anti-tumor activity of Larrea divaricata and nordhydroguayaretic acid (NDGA) due to their potential as a dietary supplement and food preservative, but little is known about Larrea cuneifolia. The aim of this work was to determine the antioxidant activity of extracts of L. cuneifolia and to identify its main phenolic compounds. Extracts were prepared with 50% ethanol from leaves collected in the Central Valley of Catamarca (Argentina). Total polyphenols content (TP) was determined by Folin-Ciocalteu and the phenolic identification and HPLC-PDA-ESI-MS/MS. In vitro antioxidant capacity was measured using the FRAP and DPPH chemical assays and on HepG2 and Caco2a cell lines to which oxidative stress was induced. ROS formation was determined through the dichlorofluresce in probe (DCFH) and cell viability was corroborated by Trypan Blue Test. The phenolic compounds identified were mainly derivatives of NDGA and glycosylated as well as methylated flavanols of quercetin, kaempferol, isorhamnetin, and gossipetin. TP content and antioxidant activity exceeded the values ​​reported for L. divaricata. In HepG2, a ROS reduction was observed when the extract concentration increased without affecting cell viability. In Caco2, the effect on stress was less marked and viability increased at higher concentration. L. cuneifolia is a species rich in phenolic compounds, with antioxidant properties and is a potential source of bioactive compounds for the production of functional foods.