The frequency shift noise in non-contact atomic force microscopy (NC-AFM) imaging and spectroscopy consists of thermal noise and detection system noise with an additional contribution from amplitude noise if there are significant tip–sample interactions. The total noise power spectral density D
Δ
f(f
m) is, however, not just the sum of these noise contributions. Instead its magnitude and spectral characteristics are determined by the strongly non-linear tip–sample interaction, by the coupling between the amplitude and tip–sample distance control loops of the NC-AFM system as well as by the characteristics of the phase locked loop (PLL) detector used for frequency demodulation. Here, we measure D
Δ
f(f
m) for various NC-AFM parameter settings representing realistic measurement conditions and compare experimental data to simulations based on a model of the NC-AFM system that includes the tip–sample interaction. The good agreement between predicted and measured noise spectra confirms that the model covers the relevant noise contributions and interactions. Results yield a general understanding of noise generation and propagation in the NC-AFM and provide a quantitative prediction of noise for given experimental parameters. We derive strategies for noise-optimised imaging and spectroscopy and outline a full optimisation procedure for the instrumentation and control loops.