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Drought intensity and duration are expected to increase over the coming century in the semiarid western United States due to anthropogenic climate change. Historic data indicate that megadroughts in this region have resulted in widespread ecosystem transitions. Landscape-scale monitoring with remote sensing can help land managers to track these changes. However, special considerations are required: traditional vegetation indices such as NDVI often underestimate vegetation cover in semiarid systems due to short and multimodal green pulses, extremely variable rainfall, and high soil fractions. Multi-endmember spectral mixture analysis (MESMA) may be more suitable, as it accounts for both green and non-photosynthetic soil fractions. To determine the suitability of MESMA for assessing drought vegetation dynamics in the western US, we test multiple endmember selection and model parameters for optimizing the classification of fractional cover of green vegetation (GV), non-photosynthetic vegetation (NPV), and soil (S) in semiarid grass- and shrubland in central New Mexico. Field spectra of dominant vegetation species were collected at the Sevilleta National Wildlife Refuge over six field sessions from May–September 2019. Landsat Thematic Mapper imagery from 2009 (two years pre-drought), and Landsat Operational Land Imager imagery from 2014 (final year of drought), and 2019 (five years post-drought) was unmixed. The best fit model had high levels of agreement with reference plots for all three classes, with R2 values of 0.85 (NPV), 0.67 (GV), and 0.74 (S) respectively. Reductions in NPV and increases in GV and S were observed on the landscape after the drought event, that persisted five years after a return to normal rainfall. Results indicate that MESMA can be successfully applied for monitoring changes in relative vegetation fractions in semiarid grass and shrubland systems in New Mexico.