Individuals with rheumatoid arthritis (RA) who also have periodontitis often show reduced inflammation in periodontal tissues, likely as a consequence of anti-rheumatic therapy. This in vitro investigation explored whether common RA medications could affect the secretion of IL-8 and IL-1β by both professional and non-professional immune cells when exposed to microbial stimuli. Periodontal ligament (PDL) fibroblasts, MONO-MAC-6 monocytes, and gingival keratinocytes were treated with ibuprofen, prednisolone, or methotrexate, either alone or in combination with lysates of Fusobacterium nucleatum or Candida albicans. Cytokine levels in the supernatants were then assessed, with IL-1β measured exclusively in MONO-MAC-6 cells. Stimulation with F. nucleatum lysate triggered the most pronounced pro-inflammatory cytokine release in PDL fibroblasts and MONO-MAC-6 cells, whereas the impact of the anti-rheumatic drugs on cytokine production was generally limited. Interestingly, prednisolone enhanced IL-8 release from MONO-MAC-6 cells exposed to F. nucleatum, whereas methotrexate reduced it. Furthermore, anti-inflammatory drugs promoted the adherence of C. albicans to epithelial cells. These results highlight that, in RA patients, controlling subgingival microbial load remains essential, but anti-rheumatic therapies may influence the immune response to oral microorganisms.