Introduction: Antibiotic resistance (ABR) is a global health crisis and a significant public health challenge in Ghana. This narrative review aims to uncover the patterned landscape of ABR by systematically assessing regional heterogeneity across three key dimensions: (1) the geographic distribution and intensity of ABR surveillance and research; (2) the prevalence of ESKAPEE pathogens ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , Enterobacter species, and Escherichia coli ); and (3) the distribution of their antimicrobial resistance profiles and underlying genetic mechanisms. The review maps data from clinical, animal, and environmental sources to provide a comprehensive sub-national picture. Methods: Four online databases (PubMed, Scopus, Web of Science, and African Journals Online) were searched for relevant articles published from 2016 to 2025, a timeframe chosen to align with the development and implementation of Ghana’s first National Action Plan (NAP) on AMR (2017–2021). A narrative synthesis was conducted to collate, analyze, and map regional data on ESKAPEE pathogen prevalence, resistance patterns, and underlying genetic mechanisms. Results: A total of 48 studies met the inclusion criteria. The findings reveal a significant disparity in research coverage, with a heavy concentration of studies in the Greater Accra (35.4%) and Ashanti (18.6%) regions. Widespread multidrug resistance was evident across all studied regions, with E. coli and K. pneumoniae consistently showing high resistance (>70%) to common antibiotics like ampicillin and third-generation cephalosporins. The review documents the emergence of critical carbapenemase genes (including blaNDM-1 and blaOXA-48 ), a notable prevalence of methicillin-resistant S. aureus (MRSA), and the detection of the colistin resistance gene mcr-1 in animal sources. Significant heterogeneity in study design and methodology was observed across the included literature. Conclusion: ABR in Ghana presents as a patterned landscape rather than a uniform national profile. Stark regional disparities and major surveillance gaps create “blind spots” that can hinder the effective implementation of national policy. Addressing this requires prioritizing surveillance in under-studied regions and standardizing methodologies. Furthermore, region-specific control strategies must be developed using a “One Health” approach, one that integrates surveillance and stewardship interventions across human healthcare, agricultural, and environmental sectors.