AbstractAnthropogenic activities have drastically impacted the climate system since the Industrial Revolution. However, to what extent anthropogenic emissions influence the cloud droplet number concentration (Nd), the critical parameter for understanding aerosol‐cloud interactions, is poorly known on the hemispheric scale due to the considerable retrieval uncertainty. We employed multiple widely used Nd retrieval sampling methods to evaluate the long‐term trend in Nd contrast (ΔNd(NH‐SH)) between the Northern Hemisphere (NH) and Southern Hemisphere (SH). Here we show that the ΔNd(NH‐SH) was halved from 2003 to 2020 using different sampling methods and channels, even though the range of magnitudes of ΔNd(NH‐SH) from different retrieval sampling methods is large. Such dramatic changes in ΔNd(NH‐SH) are dominated by the significantly decreased Nd over the NH (∼20%) due to emission reductions compared to the relatively stable and pristine nature of the SH. Aerosol optical depth (AOD) and aerosol index (AI) correlate poorly with Nd based on long‐term trends, even though they replicate the contrast trends. This poor correlation is partly contributed by stratospheric smoke from wildfires in Australia that had little influence on Nd in the SH. The northwest Atlantic shows the largest contribution, ∼38%, to the Nd trend, whereas the northwest Pacific dominates the change in AOD and AI, contributing more than 60% to AOD and ∼50% to the AI trend in the NH. Our results imply that emission reductions significantly reduced ΔNd(NH‐SH) and provide strong observational evidence that anthropogenic activities have extensively altered liquid clouds in the NH in the last two decades.