Abstract Pentagonal two‐dimensional (2D) materials are notable for unique properties derived from their Cairo pentagonal tiling topology. This study explores the thermoelectric potential of exfoliated penta‐palladium‐phosphorus‐sulfur (PdPS) atomic layers, an air‐stable 2D semiconductor with a puckered pentagonal low‐symmetry structure, grown via chemical vapor transport (CVT). Thickness‐dependent in‐plane electrical conductivity (σ) and thermoelectric power factor ( PF ) of PdPS are investigated from 20–380 K, showing an increase in σ with thickness (11, 13, and 88‐layer). Applying back‐gate voltage (V g ) modulates the Fermi energy ( E F ), and as V g decreases, the Seebeck coefficient ( S ) rises, achieving S of −700 µV K −1 for 11‐layer PdPS at −10 V, significantly higher than the −400 µV K −1 for 88‐layer PdPS. The PF increased with decreasing thickness, peaking at ≈50 µW m −1 K −2 for 11‐layer PdPS, about twice than that of 88‐layer PdPS. The high electron mobility (µ e ) in PdPS is confined to a narrow temperature range, peaking at 300 cm 2 Vs −1 at 100 K, marking the transition temperature from ionized impurity scattering to acoustic phonon scattering mechanism, consistent across all layer counts. This work highlights the significant impact of quantum confinement in ultrathin bodies in enhancing thermoelectric performance across a wide temperature range.