Gastric　cancer　remains　a　major　cause　of　mortality.　The　current　standard　of　care　of　gastric　cancer　is　based　upon　combination　chemotherapy　comprising　platinum,　fluoropyrimidines　drugs　and　docetaxel.　However,　the　efficacy　of　chemotherapy　is　hindered　by　intrinsic　and　acquired　drug　resistance,　resulting　in　poor　patient　prognosis.　Studies　are　currently　exploring　the　potential　of　immunotherapy　and　other　biologically　targeted　agents　in　the　perioperative　setting.　To　select　the　most　efficacious　therapy　for　advanced　gastric　cancer,　including　adenocarcinoma　of　the　esophago-gastric　junction,　it　is　essential　to　determine　key　biomarkers　including　for　example　human　epidermal　growth　factor　receptor　2　(HER2)　expression,　programmed　death-ligand　1　(PD-L1)　combined　positive　score　(CPS),　Claudin　18.2,　and　microsatellite　instability　(MSI).　Moreover,　recent　studies　have　highlighted　the　potential　of　natural　products　as　effective　agents　in　surmounting　anticancer　drug　resistance　in　gastric　cancer.　These　bioactive　compounds　exhibit　various　antitumor　activities,　including　induction　of　apoptosis,　inhibition　of　cell　proliferation,　modulation　of　autophagy,　and　most　importantly　reversal　of　distinct　multidrug　resistance　(MDR)　modalities.　The　present　review　provides　a　comprehensive　analysis　of　the　mechanisms　underlying　chemoresistance　in　gastric　cancer　and　explores　how　natural　products　can　overcome　distinct　MDR　mechanisms.　We　further　discuss　the　therapeutic　potential　of　combining　natural　products　with　established　chemotherapeutics　and　immunotherapy　agents　to　enhance　treatment　efficacy　and　reduce　adverse　effects.