Background: Pediatric dental crowns play an integral role as they maintain the form and function and prolong the life of the affected tooth. However, placing a crown in the oral cavity creates a new niche for the adhesion of microorganisms that can lead to plaque accumulation, gingival inflammation, and the development of secondary caries, which in the long term might determine the clinical success of the restored tooth. The present study allowed us to assess the changes caused by the full coverage restorations at a clinical, immunological, and microbiological level using enzyme-linked immunosorbent assay (ELISA) and microbial analysis. Materials and methods: The in vivo analysis consisted of a total of 26 children aged 3–10 years. They were divided into two groups, group I (n = 13) children receiving preformed zirconia crowns and group II receiving stainless steel crowns (SSCs). Plaque index (PI) scores, gingival index (GI) scores, and interleukin-6 (IL-6) levels were assessed at baseline and at 45 days of follow-up. The in vitro part of the study consisted of 13 preformed zirconia crowns and 13 SSCs which were immersed in artificial saliva containing strains of Lactobacillus casei which were then processed for their microbial analysis. Results: On mean comparison, preformed zirconia crowns performed superiorly both clinically and immunologically compared to SSCs. Microbial analysis using independent t-test revealed that the colony-forming units (CFU) per milliliter was statistically significantly higher for the SSCs, and the mean difference among the groups was statistically significant (p < 0.01). Conclusion: Preformed zirconia crowns can be a relative replacement for SSCs in primary teeth with the advantage of esthetics and superior periodontal health.