Periodontitis is associated with vascular endothelial dysfunction and elevated cardiovascular risk, but the mechanisms by which Porphyromonas gingivalis-derived lipopolysaccharide (Pg. LPS) impair endothelial function remain poorly understood. We investigated whether Pg. LPS disrupts endothelial homeostasis through oxidative stress, tetrahydrobiopterin (BH₄) metabolism, nitric oxide signaling, and glucose metabolism in primary human umbilical vein endothelial cells (HUVECs). In addition, we evaluated the protective effects of L-sepiapterin (a BH₄ precursor) and the Nrf2 activator CDDO-Me. HUVECs were treated in vitro with Pg. LPS (10 μg/mL) for 12, 24, or 48 h, with or without L-sepiapterin (100 μM) or CDDO-Me (100 nM), and outcomes were assessed by qRT-PCR, Western blot, ELISA, and biochemical assays. Pg. LPS activated TLR4/NF-κB signaling, increased ROS and ICAM-1, suppressed Nrf2. It produced a biphasic disruption of GCH1/DHFR expression; reduced extracellular BH₄, eNOS expression, and eNOS dimerization; increased iNOS expression; altered nitrite output; and increased PEA-15 and GLUT1 expression and glucose uptake. L-Sepiapterin more consistently restored BH₄ and eNOS coupling, whereas CDDO-Me more effectively suppressed iNOS and oxidative/inflammatory markers. These findings identify disruption of the GCH1/DHFR–BH₄–eNOS axis as a key mechanism of Pg. LPS-induced endothelial dysfunction and suggest that targeting BH₄ metabolism and Nrf2 signaling may be complementary therapeutic strategies for periodontitis-associated vascular disease.