This study analyzed the spatiotemporal trends of resistance to non-β-lactam antibiotics among community-onset Staphylococcus aureus (S. aureus) infections in the U.S. from 2010 to 2019 using data from Veterans Health Administration (VHA) outpatient clinics. A total of 382,149 S. aureus isolates from 268,214 unique outpatients were examined. The study found a nationwide decrease in methicillin-resistant S. aureus (MRSA) prevalence, from 53.6% in 2010 to 38.8% in 2019. Among MRSA isolates, resistance to tetracyclines and trimethoprim-sulfamethoxazole (TMP-SMX) increased significantly, while resistance to macrolides decreased. For methicillin-sensitive S. aureus (MSSA), resistance to clindamycin, tetracyclines, and TMP-SMX increased. Regional variations were observed, with the South showing higher resistance rates to tetracyclines and TMP-SMX, particularly in MRSA isolates. Bivariate mapping at the county level showed limited spatial overlap in high resistance rates for the four antimicrobial classes. The study highlights the need for tailored prescribing practices based on local resistance trends. It also suggests that geographic variation in resistance patterns should inform empirical therapy recommendations. The findings indicate that while resistance to non-β-lactam antibiotics has increased in some areas, there is no widespread co-occurrence of high resistance to multiple classes. The study underscores the importance of spatially explicit surveillance to better understand and manage antimicrobial resistance in S. aureus infections.This study analyzed the spatiotemporal trends of resistance to non-β-lactam antibiotics among community-onset Staphylococcus aureus (S. aureus) infections in the U.S. from 2010 to 2019 using data from Veterans Health Administration (VHA) outpatient clinics. A total of 382,149 S. aureus isolates from 268,214 unique outpatients were examined. The study found a nationwide decrease in methicillin-resistant S. aureus (MRSA) prevalence, from 53.6% in 2010 to 38.8% in 2019. Among MRSA isolates, resistance to tetracyclines and trimethoprim-sulfamethoxazole (TMP-SMX) increased significantly, while resistance to macrolides decreased. For methicillin-sensitive S. aureus (MSSA), resistance to clindamycin, tetracyclines, and TMP-SMX increased. Regional variations were observed, with the South showing higher resistance rates to tetracyclines and TMP-SMX, particularly in MRSA isolates. Bivariate mapping at the county level showed limited spatial overlap in high resistance rates for the four antimicrobial classes. The study highlights the need for tailored prescribing practices based on local resistance trends. It also suggests that geographic variation in resistance patterns should inform empirical therapy recommendations. The findings indicate that while resistance to non-β-lactam antibiotics has increased in some areas, there is no widespread co-occurrence of high resistance to multiple classes. The study underscores the importance of spatially explicit surveillance to better understand and manage antimicrobial resistance in S. aureus infections.