Two-dimensional molybdenum disulfide (MoS2) is one of the most promising candidates for next-generation semiconductors. Among the advantages offered by MoS2, a tunable bandgap that depends on the thickness is essential for the on-demand manufacturing of nanoelectronics. For this reason, elaborate layer control of MoS2 has been a long-standing research objective. However, prior efforts had several critical issues including surface roughness, poor uniformity/scalability, and impurities. Through this study, we aimed to achieve both ultrahigh precision and purity in large-scale (4 in.) layer control of MoS2 by two consecutive plasma processes: plasma-enhanced chemical vapor deposition (PECVD) and reactive ion etching (RIE). The 4 in. wafer-scale MoS2 was synthesized by PECVD, and the as-grown bulk layers were etched using RIE with a computationally screened gas mixture in the cyclic step. For every RIE cycle, the 4 in. MoS2 wafer was evenly etched to a thickness of 0.3–0.4 nm while there was no damage to the atomic structure and chemical impurities. For the computational screening of candidate gases, first-principles calculations explored the energetics of surface reaction and offered physical insights into the associated electronic interaction. The combination of computational screening and experimentation accelerates optimal process design and provides an in-depth understanding of the plasma–surface interactions.