Second-line chemotherapy is recommended for patients who have disease progression after first-line chemotherapy and have a good performance status. The aim of our study is thus to determine which chemotherapy regimen is more appropriate for second-line gastric cancer treatment. Patients were included if they met the following inclusion criteria: metastatic gastric adenocarcinoma pathology; no previous treatment for local gastric cancer (surgery, chemotherapy, or radiotherapy); received first-line chemotherapy for metastatic gastric cancer and had the disease progress afterward; had adequate organ functions for second-line chemotherapy; had an Eastern Cooperative Oncology Group (ECOG) score 0–2; and were HER-2 negative. The patients were examined in three groups according to the second-line chemotherapy regimen they received. These three groups were compared in terms of overall and progression-free survival. The three groups were statistically similar in overall survival, which was the primary endpoint of the study; the median overall survival was 5 months in the FOLFIRI group (n = 79), 6.5 months in the platinum-based group (n = 55), and 5.6 months in the taxane-based group (n = 40) (p = 0.554). There was no statistical difference between the groups’ progression-free survival either; the median progression-free survival time was 3.43 months in the FOLFIRI group, 4 months in the platinum-based group, and 2.77 months in the taxane-based group (p = 0.546). There was no statistically significant difference between the three irinotecan-based, platinum-based, and taxane-based treatments. According to our study’s results, the chemotherapy given in second-line treatment should be decided on an individual basis according to toxicity and cost.