We aimed to test the anti-inflammatory and angiogenic properties of two different thermal waters at the cellular level in human keratinocyte cells in the present study. Two different thermal waters, thermo-mineral BJ1 (Bursa, Turkey) and oligomineral BG (Bolu, Turkey), were tested in human keratinocyte (HaCaT) cell line. HaCaT cells were incubated for 3 days with thermal waters; RNA isolation was carried out in the treated and untreated cells. The gene expressions of TNFα, IL-1α, and VEGF were measured using the RT-qPCR. The tested thermal waters significantly decreased the expression of IL-1α (BJ1 93% p = 0.0024 and BG 38% p = 0.0303). BJ1 and BG thermal waters downregulated the expression of TNFα (59% p = 0.0001 and 23% p = 0.0238 respectively). Furthermore, BJ1 and BG significantly downregulated the gene expression of VEGF (98% p = 0.0430 and 15% p = 0.0120). The observed decrease in the gene expression of TNFα and IL1α could be interpreted as an anti-inflammatory effect of mineral waters on HaCaT cells. Moreover, the suppressed VEGF expression might be an indicator of the antiangiogenic effect on human keratinocytes. Therefore, we hypothesized that depending on their specific chemical composition such as silica (128 mg/L) in BJ1 and hydrogen sulfide (1.2 mg/L) in BG, thermal waters suppress pro-inflammatory cytokines and angiogenic growth factor. These preliminary findings might give insight on the underlying mechanisms of the therapeutic benefits observed in some skin diseases such as rosacea and psoriasis.