An optimal host–microbiota interaction in the human vagina governs the reproductive health status of a woman. The marked depletion in the beneficial Lactobacillus sp. increases the risk of infection with sexually transmitted pathogens, resulting in gynaecological issues. Vaginal infections that are becoming increasingly prevalent, especially among women of reproductive age, require an effective concentration of antimicrobial drugs at the infectious sites for complete disease eradication. Thus, topical treatment is recommended as it allows direct therapeutic action, reduced drug doses and side effects, and self-insertion. However, the alterations in the physiological conditions of the vagina affect the effectiveness of vaginal drug delivery considerably. Conventional vaginal dosage forms are often linked to low retention time in the vagina and discomfort which significantly reduces patient compliance. The lack of optimal prevention and treatment approaches have contributed to the unacceptably high rate of recurrence for vaginal diseases. To combat these limitations, several novel approaches including nano-systems, mucoadhesive polymeric systems, and stimuli-responsive systems have been developed in recent years. This review discusses and summarises the recent research progress of these novel approaches for vaginal drug delivery against various vaginal diseases. An overview of the concept and challenges of vaginal infections, anatomy and physiology of the vagina, and barriers to vaginal drug delivery are also addressed.