Background: The challenge of emerging antimicrobial resistance and variation in antibiotic use across provinces in China call for knowledge on antibiotic utilization at the regional level. This study aims to evaluate the long-term trends and patterns of antibiotic usage in Xinjiang Province, the largest provincial-level division located in the northwest of China, aiming to provide evidence in enhancing provincial antimicrobial stewardship (AMS) and developing policy measures to optimize regional antimicrobial use. Methods: This was an ecological study with temporal trend analysis on inpatient antibiotic utilization, with antibiotic use data from 92 public hospitals covered by Xinjiang’s Center for Antibacterial Surveillance from 2012 to 2022. Antibiotic use was measured by the number of daily defined doses per 100 patient days (DDDs/100 pds). Patterns of antibiotic use were described by Anatomical Therapeutic Chemical (ATC) subgroups and the Access, Watch, Reserve (AWaRe) classification. The Average Annual Percent Change (AAPC) of antibiotic use and the corresponding 95% confidence intervals (CIs) were calculated to describe the trend of antibiotic use over time. Joinpoint regression was performed using the Weighted Bayesian Information Criteria (WBIC) model with a parametric method. A pairwise comparison between secondary and tertiary hospitals was conducted to explore disparities in antibiotic use across hospital levels. The most commonly used antibiotics were also analyzed. Results: The total inpatient antibiotic use in Xinjiang was 27.6 DDDs/100 patient days in 2022, with a significant decreasing trend during 2012–2022 (AAPC, −2.0%; 95% CI, −3.6% to −0.4%). The Watch group antibiotics were the most used AWaRe category, with the Access-to-Watch ratio decreasing significantly from 46.4% to 24.4% (AAPC, −6.8%; 95% CI, −8.4% to −5.1%). No significant difference was found in the trend of total antibiotic use between secondary and tertiary hospitals, but there were disparities across hospital levels in subgroups. Third-generation cephalosporins, second-generation cephalosporins, and fluoroquinolones remained the top three antibiotic class throughout the study period. The number of antibiotics accounting for 90% of the total antibiotic use decreased from 34 antibiotics in 2012 to 18 antibiotics in 2022. Conclusions: The decreasing trend of inpatient antibiotic use in Xinjiang’s public hospitals reflects the effects of continuous AMS implementation. Patterns of antibiotic use underscore the need for further efforts on evidence-based antibiotic selection and for analyses on the appropriateness of antibiotic use.