Aim: This study aimed to compare the histopathological characteristics of nasopharyngeal carcinoma (NPC) in smokers and non-smokers, with a focus on tumor type, morphological features, and tumor microenvironment. Additionally, the study evaluated the correlation between smoking intensity and histopathological parameters. Materials and Methods: A retrospective study was conducted on 160 NPC patients, divided into two groups: smokers (n = 80) and non-smokers (n = 80). Demographic, clinical, and histopathological data were collected and analyzed. Tumor type, morphological features, and microenvironmental characteristics were examined using the World Health Organization classification and specific histological markers. Statistical tests, including chi-square and Pearson's correlation, were used to assess differences and correlations, with a p-value of <0.05 considered significant. Results: Smokers had a higher prevalence of keratinizing squamous cell carcinoma (25.00%) compared to non-smokers (10.00%, p = 0.013). Non-keratinizing differentiated carcinoma was more common in non-smokers (62.50%) than smokers (43.75%, p = 0.027). Smokers exhibited higher keratinization (31.25% vs. 12.50%, p = 0.008), reduced lymphoid stroma (62.50% vs. 87.50%, p = 0.001), and a trend toward advanced-stage disease (Stage IV: 31.25% vs. 18.75%, p = 0.083). Smoking intensity was negatively correlated with tumor differentiation (r = -0.32, p = 0.002) and lymphoid stroma (r = -0.25, p = 0.018) but positively correlated with keratinization (r = 0.45, p < 0.001) and necrosis (r = 0.22, p = 0.025). Conclusion: This study revealed significant histopathological differences in NPC between smokers and non-smokers. Smoking was associated with more aggressive histopathological features, including keratinization, reduced lymphoid stroma, and poorer differentiation. These findings highlight the need for targeted prevention and personalized treatment strategies for smokers with NPC.