The medicinal plants of the desert can be a potential source of natural bioactive compounds with applications in health and food preservation. This work aimed to investigate the phenolic content and antioxidant potential of twenty-three plants from the arid zone of Viesca, Mexico. The antioxidant potential was determined by three methods (ABTS, FRAP, and DPPH). Two extraction methods and three different concentration levels (1:10 mg/mL, 1:25 mg/mL, and 1:50 mg/mL) were evaluated. According to the results, Turnera diffusa (Damiana), Gutierrezia sarothrae (Hierba de San Nicolas), and Leucophyllum frutescens (Cenizo) present the largest content of phenolic compounds and high antioxidant activity. The highest values of antioxidant activity were achieved using a solid/liquid ratio of 1:50 g/mL for T. diffusa and G. sarothrae and 1:25 mg/mL for L. frutescens. The maceration method was the most suitable for extracting antioxidant compounds from T. diffusa and L. frutescens, while ultrasound-assisted extraction was more efficient for G. sarothrae. The HPLC-MS analysis showed the presence of important phenolic compounds. This study shows for the first time that three plants that naturally grow in Viesca have great potential as a source of natural antioxidant compounds.