jats:titleAbstract</jats:title> jats:pWe report the discovery of an extreme galaxy overdensity at jats:italicz</jats:italic> = 5.4 in the GOODS-S field using James Webb Space Telescope (JWST)/NIRCam imaging from JADES and JEMS alongside JWST/NIRCam wide-field slitless spectroscopy from FRESCO. We identified potential members of the overdensity using Hubble Space Telescope+JWST photometry spanning jats:italicλ</jats:italic> = 0.4–5.0 jats:italicμ</jats:italic>m. These data provide accurate and well-constrained photometric redshifts down to jats:italicm</jats:italic> ≈ 29–30 mag. We subsequently confirmed jats:italicN</jats:italic> = 81 galaxies at 5.2 < jats:italicz</jats:italic> < 5.5 using JWST slitless spectroscopy over jats:italicλ</jats:italic> = 3.9–5.0 jats:italicμ</jats:italic>m through a targeted line search for Hjats:italicα</jats:italic> around the best-fit photometric redshift. We verified that jats:italicN</jats:italic> = 42 of these galaxies reside in the field, while jats:italicN</jats:italic> = 39 galaxies reside in a density around ∼10 times that of a random volume. Stellar populations for these galaxies were inferred from the photometry and used to construct the star-forming main sequence, where protocluster members appeared more massive and exhibited earlier star formation (and thus older stellar populations) when compared to their field galaxy counterparts. We estimate the total halo mass of this large-scale structure to be jats:inline-formula jats:tex-math

</jats:tex-math> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> mml:mn12.6</mml:mn> mml:mo≲</mml:mo> mml:msub mml:mrow mml:milog</mml:mi> </mml:mrow> mml:mrow mml:mn10</mml:mn> </mml:mrow> </mml:msub> <mml:mfenced close=")" open="("> mml:mrow mml:msub mml:mrow mml:miM</mml:mi> </mml:mrow> mml:mrow mml:mihalo</mml:mi> </mml:mrow> </mml:msub> mml:mrow <mml:mo stretchy="true">/</mml:mo> </mml:mrow> mml:msub mml:mrow mml:miM</mml:mi> </mml:mrow> mml:mrow mml:mo⊙</mml:mo> </mml:mrow> </mml:msub> </mml:mrow> </mml:mfenced> mml:mo≲</mml:mo> mml:mn12.8</mml:mn> </mml:math> </jats:inline-formula> using an empirical stellar mass to halo mass relation, which is likely an underestimate as a result of incompleteness. Our discovery demonstrates the power of JWST at constraining dark matter halo assembly and galaxy formation at very early cosmic times.</jats:p>