Background Proton pump inhibitors (PPIs) are widely-used over-the-counter drugs. However, possible, and quite ambiguous, interaction has been suggested between capecitabine and PPIs; with some discrepancy still being present within the literature regarding the possible risks, or even benefits, of their concomitant use. This meta-analysis therefore aims to analyze data from the literature regarding both the risk of PPIs on survival in patients treated with capecitabine, as well as their benefit regarding the incidence of hand foot syndrome (HFS). Methods 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. Results 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 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. Conclusion Individual data incriminating the use of PPIs with capecitabine is quite limited; however, our robust survival data on around 30,000 patients gave significant worse survival outcomes, particularly in the (neo)adjuvant setting.