Background Megaloblastic anemia (MA) occurs due to ineffective erythropoiesis, which results from impaired DNA synthesis in the hematopoietic precursors and intramedullary hemolysis. MA’s most common cause is nutritional deficiencies of either cobalamin (vitamin B12) or folate (vitamin B6). This study aims to determine the association between MA caused by vitamin B12 deficiency and psychosis among psychotic male patients in Mental Health Hospital at Taif, Saudi Arabia. Methods Fifty psychotic male patients, aged 48.58±1.72, were recruited from the Mental Health Hospital at Taif, Saudi Arabia, in addition to 54 sex-matched healthy controls. The following tests were run: complete blood count (CBC), liver function tests (LFT), serum levels of vitamin B12, folate, and C-reactive protein (CRP). Results The CBC showed that RBCs count, haemoglobin, haematocrit, platelets count, mean platelets volume (MPV), and absolute lymphocyte count were significantly lower in psychotic patients versus healthy controls (P=0.007, P=0.002, P=0.001, P=0.004, P=0.0001, and P=0.005, respectively). In contrast, the eosinophil absolute count and basophil percentage were significantly higher in psychotic patients versus controls (P=0.009, P=0.0001, respectively). Vitamin B12 levels were insignificantly decreased in psychotic patients versus healthy group. There were significant negative correlations between serum levels of VitB12 and negative symptoms (r=−0.381, P=0.006) and hallucination (r=−0.297, P=0.036). Conclusion These findings indicate no link between MA induced by VitB12 insufficiency and psychosis among psychotic patients. However, low serum VitB12 can predict the severity of some psychosis signs, including hallucinations and negative symptoms. Therefore, monitoring VitB12 levels and its supplementation in psychotic patients is recommended to improve their symptoms.