Spin-crossover (SCO) is generally regarded as a spectacular molecular magnetism in 3d(4)-3d(7) metal complexes and holds great promise for various applications such as memory, displays, and sensors. In particular, SCO materials can be multifunctional when a classical light- or temperature induced SCO occurs along with other cooperative structural and/or electrical transport alterations. However, such a cooperative SCO has rarely been observed in condensed matter under hydrostatic pressure (an alternative external stimulus to light or temperature), probably due to the lack of synergy between metal neighbors under compression. Here, we report the observation of a pressure-driven, cooperative SCO in the two-dimensional (2D) honeycomb antiferromagnets MnPS3 and MnPSe3 at room temperature. Applying pressure to this confined 2D system leads to a dramatic magnetic moment collapse of Mn2+ (d(5)) from S = 5/2 to S = 1/2. Significantly, a number of collective phenomena were observed along with the SCO, including a large lattice collapse (similar to 20% in volume), the formation of metallic bonding, and a semiconductor-to-metal transition. Experimental evidence shows that all of these events occur in the honeycomb lattice, indicating a strongly cooperative mechanism that facilitates the occurrence of the abrupt pressure-driven SCO. We believe that the observation of this cooperative pressure-driven SCO in a 2D system can provide a rare model for theoretical investigations and lead to the discovery of more pressure-responsive multifunctional materials.