Background: Asthma is a common chronic respiratory disorder that induces cytological alterations in the airways and oral mucosa. Persistent inflammation and long-term inhalation therapy may contribute to epithelial hyperplasia, metaplasia, and atypia. Objective: To assess cytological changes in sputum and buccal smears among chronic asthmatic patients in Shendi, Sudan. Methods: A descriptive cross-sectional case-control study was conducted on 60 chronic asthmatic patients and 60 matched healthy controls. Sputum and buccal smears were collected, stained using the Papanicolaou technique, and examined microscopically. Data were analyzed using SPSS, and statistical significance was set at p < 0.05. Results: Nuclear atypia, inflammation, infection, cytoplasmic vacuolization, and prenuclear halos were significantly more frequent in sputum samples from asthmatic patients compared with controls (p < 0.001). Buccal smears showed increased inflammation and infection among patients, particularly those on long-term inhaled therapy, while nuclear atypia was not statistically significant. Poor housing conditions and positive family history were strongly associated with asthma prevalence. Conclusion: Chronic asthma is linked to marked cytological alterations in sputum and, to a lesser extent, buccal mucosa. These findings highlight the role of cytological screening as a simple and cost-effective tool for evaluating cellular changes in asthmatic patients.