Significance: In Sweden, where snus use exceeds smoking among men, relatively low rates of major smoking-related diseases have been recorded. However, currently published studies lack a clear consensus on the effects of snus use on oral health, mainly due to confounding factors in epidemiological data, such as lack of account for the variability of product chemistry and use patterns. In line with the aims of tobacco harm reduction strategies, the effect of snus use should be investigated in comparison with that of cigarette smoking. The present study aimed to determine the biological impact of snus extracts from CORESTA and Swedish Match, in comparison with total particulate matter (TPM) from 3R4F reference cigarette smoke, by a systems toxicology approach. Methods: Two doses of snus extracts and TPM, diluted in phosphate-buffered saline and with matched nicotine concentrations, were applied to the apical side of human gingival organotypic epithelial cultures repeatedly for 72 hours. An additional higher concentration of the snus extracts was included to reflect nicotine levels observed in the saliva of snus users. Results: Gingival tissue morphology and medium levels of inflammatory mediators indicated a mild, transient effect of snus extract exposure compared with overt tissue injury elicited by TPM. Network enrichment analysis using the profiles of differentially expressed genes and causal biological network models demonstrated a lower impact of the snus extracts on the biological processes captured in the network models, particularly the xenobiotic metabolism response network, compared with that exerted by TPM. An integrative analysis of the mRNA and miRNA expression profiles was performed, providing novel exposure markers and suggesting potential roles for the miRNA involved in biological alterations. Conclusions: These data indicate that exposure to snus extract, even at considerably higher nicotine concentrations, has less impact on the gingival epithelium than cigarette smoke exposure. Although this study did not fully account for the repeated exposure occurring in snus users, it supports the harm reduction potential of snus in the context of oral health.