Proton pump inhibitors (PPIs) are widely used over-the-counter drugs. The interaction between capecitabine and PPIs is still ambiguous within the literature, with some discrepancies still being present regarding the risks, or benefits, of their concomitant use. This meta-analysis aims to analyse data from the literature regarding both the risk of PPIs on survival in patients treated with capecitabine, as well as their benefits regarding the incidence of hand-foot syndrome (HFS). A total of 17 studies were included after searching PubMed, Medline and Cochrane until October 2022 for the effect of PPIs on the treatment efficacy and pharmacokinetics, and incidence of HFS. Revman Ver. 5.3 was used for all statistical analyses. Our data showed a significant HFS reduction at a relative risk of 0.77 (95% CI: 0.70–085; p < 0.00001) in the PPI-using groups compared to control. Meta-analysis of studies assessing survival, however, showed a reduction in almost all survival aspects, most notably within the recurrence-free survival, with a hazard ratio of 1.75; 95% CI: 1.21–2.53; p = 0.003. Individual data incriminating the use of PPIs with capecitabine is quite limited; however, our robust survival data on around 30,000 patients gave significantly worse survival outcomes, particularly in the (neo)adjuvant setting.