Background/Objectives: The rise of multidrug-resistant pathogens complicates the management of urinary tract infections (UTIs), particularly in empirical antibiotic therapy. This study aimed to develop Weighted Incidence Syndromic Combination Antibiogram (WISCA) models to optimize antibiotic therapy for adult patients with community-onset UTIs presenting to emergency care settings at our institution. Methods: A retrospective study was conducted using a hierarchical Bayesian model to develop WISCA models for UTI management. Data were extracted from microbiology laboratory records and medical databases, focusing on adult patients stratified by age, prior antibiotic exposure, and clinical characteristics. Clinical outcomes, such as extended hospital stays and in-hospital mortality, were evaluated before WISCA model development. Eleven monotherapies and 18 combination therapies were tested against 15 pathogens, with posterior coverage probabilities and 95% highest density intervals (HDIs) used to assess antibiotic coverage. Results: Inappropriate antibiotic treatment (both empirical and directed) was initially associated with worse clinical outcomes. After adjusting for covariates, inappropriate directed treatment during the UTI episode was significantly associated with in-hospital mortality, highlighting the need for tailored therapeutic strategies. WISCA models provided robust estimates of antibiotic coverage probabilities, revealing subgroup differences. Combination regimens demonstrated superior coverage, particularly in patients with multidrug-resistant pathogens, older adults, and those with conditions linked to MDR organisms. Conclusions: WISCA models show promise in optimizing antibiotic selection for UTIs requiring hospitalization by integrating local resistance patterns and patient-specific factors. These findings support WISCA-informed strategies to potentially improve clinical outcomes and mitigate antibiotic resistance in UTIs.