Friction phenomena in two-dimensional (2D) materials are conventionally studied at atomic length scales in a few layers using low-load techniques. However, the advancement of 2D materials for semiconductor and electronic applications requires an understanding of friction and delamination at a few micrometers length scale and hundreds of layers. To bridge this gap, the present study investigates frictional resistance and delamination mechanisms in 2D tungsten diselenide (WSe2) at 10 µm length and 100–500 nm depths using an integrated atomic force microscopy (AFM), high-load nanoscratch, and in-situ scanning electron microscopic (SEM) observations. AFM revealed a heterogenous distribution of frictional resistance in a single WSe2 layer originating from surface ripples, with the mean increasing from 8.7 to 79.1 nN as the imposed force increased from 20 to 80 nN. High-load in-situ nano-scratch tests delineated the role of the individual layers in the mechanism of multi-layer delamination under an SEM. Delamination during scratch consists of stick-slip motion with friction force increasing in each successive slip, manifested as increasing slope of lateral force curves with scratch depth from 10.9 to 13.0 (× 103) Nm−1. Delamination is followed by cyclic fracture of WSe2 layers where the puckering effect results in adherence of layers to the nanoscratch probe, increasing the local maximum of lateral force from 89.3 to 205.6 µN. This establishment of the interconnectedness between friction in single-layer and delamination at hundreds of layers harbors the potential for utilizing these materials in semiconductor devices with reduced energy losses and enhanced performance.