The effect of climate factors (temperature, humidity, precipitation, and frost days) on the population changes, damage, and infestation area of the leopard moth, Zeuzera pyrina L., was studied during 2006–2018 in four parts of Iran including Saman, Arak, Najaf-abad, and Baft. For trend analysis, the Mann–Kendall test was run on time series data of both climate and pest population. According to the results, the annual mean (Kendall's statistics, T = 0.64 and 0.48), annual minimum (T = 0.60 and 0.42), and January mean (T = 0.64 and 0.61, respectively) temperatures showed increasing trends in Saman and Najaf-abad. Moreover, the annual mean minimum and January temperatures (T = 0.41 and 0.45, respectively) in Arak and the annual mean maximum temperature (T = 0.79) in Baft showed increasing trends. The number of frost days/year (Kendall's statistics, T = −0.63, −0.53, −0.32 and −0.37) and annual mean relative humidity (T = −0.43, −0.63, −0.64 and −0.42, respectively) showed decreasing trends in Saman, Arak, Baft, and Najaf-abad stations. Trend analysis indicated significant increases in the mean number of moths caught (T = 0.59, 0.76 and 0.90), the percentage of infested branches/tree (T = 0.66, 0.58, and 0.90), the number of active holes/tree (T = 0.79, 0.55, and 0.68) and the infested areas (T = 0.99, 0.73, and 0.98, respectively) in Saman, Arak and Najaf-abad stations. According to stepwise regression, the mean temperatures of January, autumn, and winter were the most effective variables for increasing Z. pyrina damage and population, while relative humidity and the number of frost days played the major role in reducing it.