On March 1, 2012, the Chinese government implemented the Administrative Measures on Heatstroke Prevention (AMHP2012) to combat the occupational health impacts of extreme heat, and reducing occupational injury was one of the main purposes. This study aimed at quantifying the intervention effects of the AMHP2012 on extreme heat-related occupational injuries and subsequent insurance payouts in Guangzhou, China. Data on occupational injuries and insurance payouts were collected from March 1, 2011, to February 28, 2013, from the occupational injury insurance system of Guangzhou. A quasi-experimental design with before-after control was adopted. Interrupted time series analysis was performed to quantify the change of occupational injuries and insurance payouts after policy implementation. The distributed lag non-linear model was used to explore whether injury claims and insurance payouts due to extreme heat decreased. A total of 9851 injury claims were included in the analysis. After policy implementation, the risk of occupational injuries and insurance payouts decreased by 13% (RR = 0.87, 95%CI: 0.75, 0.99) and 24% (RR = 0.76, 95% CI: 0.58, 0.94), respectively. The attributable fraction of extreme heat-related occupational injuries decreased from 3.17% (95%eCI: 1.35, 4.69) to 1.52% (95%eCI: −0.36, 3.15), which contributed to 0.86 million USD reduction of insurance payouts. Both males and females, low-educated, young and middle-aged workers, workers at small or medium-sized enterprises, engaging in manufacturing, and with both minor and severe injuries were apparently associated with decreased rates of extreme heat-related occupational injuries. The AMHP2012 policy contributed to the reduction of extreme heat-related occupational injuries and insurance payouts in Guangzhou, China, and this research provided novel evidence for decision-makers to better understand the necessity of implementing health protection policies among laborers under climate change.