While previous studies have suggested a substantial role of ozone‐depleting substances (ODSs) in historical climate change, their relative contribution to historical anthropogenic warming has not been quantified before. Analyzing all‐but‐one‐forcing, 20‐member ensembles of historical simulations with a state‐of‐the‐art Earth System Model, we find that over the 1955–2005 period ODSs are responsible for 30% of global warming, 37% of Arctic warming, and 33% of summertime Arctic sea ice loss. Effective Radiative Forcing (ERF) calculations reveal that the global warming response to ODSs per unit of ERF is about 20% larger than for CO2, which may be due to stronger feedbacks and the difference in temporal evolution with ODSs having leveled off and CO2 still increasing in 2005. While the response to both peaks in the Arctic, the ODS ERF opposes Arctic amplification more than the CO2 ERF. Our findings highlight the importance of the Montreal Protocol for mitigating future climate change. Plain Language Summary Ozone‐depleting substances (ODSs) are chemicals developed in the 1920s and 1930s for use in spray cans, refrigerators and plastic foams. Their commercial use increased rapidly in the 1950s and 1960s, but their phase out is underway since the signing of the Montreal Protocol in the 1987, following the identification of their devastating impact on the stratospheric ozone layer. It is well known that ODSs are powerful greenhouse gases, with the second largest warming effect between 1955 and 2005. However, their relative contribution to past global warming has not been quantified previously using comprehensive climate models. Here we show that ODSs were responsible for roughly a third of late 20th Century global warming, Arctic warming and Arctic sea ice decline. In addition, we find that the impact of ODSs on global temperatures is about 20% larger than expected based on the impacts they have on the radiative balance. The impacts of ODSs peak in the Arctic, while their radiative forcing peaks in the tropics, and thus opposes Arctic warming amplification. These findings enhance our understanding of drivers of past climate change, and highlight the importance of the Montreal Protocol for future climate change mitigation. Key Points Between 1955 and 2005, global warming from ozone‐depleting substances (ODSs) was more than half of that due to CO2, and about one third of total anthropogenic warming ODSs have been about 20% more effective than CO2 at causing global warming per unit radiative forcing ODS warming peaks in the Arctic and is 66% of that due to CO2, while their Effective Radiative Forcing (ERF) opposes Arctic amplification more than the CO2 ERF