Background: Firm conclusions about whether long-term proton pump inhibitor (PPI) drug use impacts female cancer risk remain controversial. Objective: We aimed to investigate the associations between PPI use and female cancer risks. Methods: A nationwide population-based, nested case-control study was conducted within Taiwan’s Health and Welfare Data Science Center’s databases (2000–2016) and linked to pathologically confirmed cancer data from the Taiwan Cancer Registry (1979–2016). Individuals without any cancer diagnosis during the 17 years of the study served as controls. Case and control patients were matched 1:4 based on age, gender, and visit date. Conditional logistic regression with 95% confidence intervals (CIs) was applied to investigate the association between PPI exposure and female cancer risks by adjusting for potential confounders such as the Charlson comorbidity index and medication usage (metformin, aspirin, and statins). Results: A total of 233,173 female cancer cases were identified, consisting of 135,437 diagnosed with breast cancer, 64,382 with cervical cancer, 19,580 with endometrial cancer, and 13,774 with ovarian cancer. After matching each case with four controls, we included 932,692 control female patients. The number of controls for patients with breast cancer, cervical cancer, endometrial cancer, and ovarian cancer was 541,748, 257,528, 78,320, and 55,096, respectively. The use of PPIs was significantly associated with reduced risk of breast cancer and ovarian cancer in groups aged 20–39 years (adjusted odds ratio (aOR): 0.69, 95%CI: 0.56–0.84; p < 0.001 and aOR: 0.58, 95%CI: 0.34–0.99; p < 0.05, respectively) and 40–64 years (aOR: 0.89, 95%CI: 0.86–0.94; p < 0.0001 and aOR: 0.87, 95%CI: 0.75–0.99; p < 0.05, respectively). PPI exposure was associated with a significant decrease in cervical and endometrial cancer risks in the group aged 40–64 years (with aOR: 0.79, 95%CI: 0.73–0.86; p < 0.0001 and aOR: 0.72, 95%CI: 0.65–0.81; p < 0.0001, respectively). In contrast, in elderly women, PPI use was found to be insignificantly associated with female cancers among users. Conclusions: Our findings, based on real-world big data, can depict a comprehensive overview of PPI usage and female cancer risk. Further clinical studies are needed to elucidate the effects of PPIs on female cancers.