Doxycycline, a second-generation tetracycline, has long occupied a central position in the management of sexually transmitted infections (STIs). Its favorable pharmacokinetic profile, broad antimicrobial spectrum, and decades of clinical experience have sustained its use against Chlamydia trachomatis, Treponema pallidum, and as part of combination regimens for Mycoplasma genitalium. Doxycycline has also been evaluated as post-exposure prophylaxis (doxy-PEP) in high-risk populations, with promising reductions in incident bacterial STIs. However, concerns remain regarding antimicrobial resistance and public health implementation. This review summarizes the pharmacological basis of doxycycline, its established and emerging roles in STI management, and the challenges associated with such prophylactic strategies.