Diphtheria, a vaccine-preventable disease, has re-emerged globally, particularly in regions with fragile health systems, low immunization coverage, and post-pandemic service disruptions. To better understand its burden across demographic groups, a systematic review was conducted to synthesize evidence on the epidemiology, clinical features, and outcomes of diphtheria. Studies published between 2018 and 2025 were reviewed, including peer-reviewed articles, surveillance reports, and outbreak investigations. Seventeen studies from Africa, Asia, Europe, and global datasets were included. In Nigeria, large-scale outbreaks were reported post-COVID-19, with Kano State alone contributing 85% of national cases, and mortality was highest among unvaccinated individuals or those with delayed access to treatment. Across Asia, particularly in India and Indonesia, children aged 6–10 years from low socioeconomic backgrounds were most affected, with case fatality rates ranging between 5.8% and 13%. Risk factors consistently included incomplete vaccination, delayed access to diphtheria antitoxin, and weak surveillance systems. Studies from Europe highlighted re-emergence among migrants and refugees, while genomic epidemiology demonstrated multiple Corynebacterium diphtheriae lineages linked to low coverage. Overall, the evidence underscores diphtheria’s persistence as a public health challenge in resource-limited settings and among vulnerable populations, highlighting the urgent need for strengthened routine immunization, timely availability of antitoxin, and improved genomic and epidemiological surveillance to mitigate future outbreaks.