Background Internationally, there are growing concerns about antimicrobial resistance. This has resulted in increased scrutiny of antibiotic prescribing trends – particularly in primary care where the majority of prescribing occurs. In England, antibiotic prescribing targets are set nationally but little is known about the local context of antibiotic prescribing. This study aimed to examine trends in antibiotic prescribing (including broad-spectrum), and the association with area-level deprivation and region in England. Methods Antibiotic prescribing data by GP surgery in England were obtained from NHS Business Service Authority for the years 2014–2018. These data were matched with the Index of Multiple Deprivation (IMD) 2015 at the Lower Layer Super Output Area level Lower Layer Super Output Area (LSOA) level. Linear regression methods were employed to explore the relationship between antibiotic use and area-level deprivation as well as region, after controlling for a range of other confounding variables, including health need, rurality, and ethnicity. Results Over time, the amount of antibiotic prescribing significantly reduced from 1.11 items per STAR-PU to 0.96 items per STAR-PU – a reduction of 13.6%. The adjusted models found that, at LSOA level, the most deprived areas of England had the highest levels of antibiotic prescribing (0.03 items per STAR-PU higher). However, broad spectrum antibiotic prescribing exceeding 10% of all antibiotic prescribing within a GP practice was higher in more affluent areas. There were also significant regional differences – with the North East and the East of England having the highest levels of antibiotic prescribing (by 0.16 items per STAR-PU). Conclusion Although antibiotic prescribing has reduced over time, there remains significant variation in by area-level deprivation and region in England – with higher antibiotic prescribing in more deprived areas. Future prescribing targets should account for local factors to ensure the most deprived communities are not inappropriately penalised.