Community-acquired skin and soft tissue infections (CA-SSTIs) are among the most common bacterial infections globally, with antimicrobial resistance (AMR) posing a growing threat to treatment efficacy. This study aimed to explore global disparities in AMR prevalence among key pathogens causing CA-SSTIs, identify region-specific risk factors, and evaluate the impact of healthcare system characteristics on AMR trends. A cross-continental observational study was conducted across 20 communities in 5 continents (North America, Asia, Europe, Africa, South America) from March 2022 to March 2024, enrolling 3,842 patients with confirmed CA-SSTIs. Microbiological culture and susceptibility testing, along with structured questionnaires, were used to collect data on pathogen distribution, AMR profiles, patient characteristics, and healthcare access. The overall prevalence of AMR among CA-SSTI pathogens was 34.6%, with significant intercontinental variations: highest in Africa (48.2%) and Asia (43.5%), followed by South America (35.1%), Europe (26.8%), and North America (22.3%). Methicillin-resistantStaphylococcus aureus (MRSA) was the most prevalent resistant pathogen globally (18.7%), with the highest prevalence in Africa (31.5%) and the lowest in North America (10.2%). Key region-specific risk factors included limited access to dermatological care (Africa, Asia), over-the-counter antimicrobial use (Asia, South America), and inadequate infection prevention practices (all regions). Healthcare system factors, such as the availability of rapid diagnostic tests (RDTs) and antimicrobial stewardship programs (ASPs) in community settings, were inversely associated with AMR prevalence. This study highlights significant global disparities in AMR among CA-SSTIs, driven by a complex interplay of patient, healthcare, and systemic factors. Targeted interventions, including expanding access to RDTs, implementing context-specific ASPs, and strengthening public health education, are critical to addressing these disparities and improving CA-SSTI treatment outcomes worldwide.