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We investigated the association between methylenetetrahydrofolate reductase (gene <i>MTHFR</i> 677C>T, rs1801133), 5-methyltetrahydrofolate-homocysteine methyltransferase (<i>MTR</i> 2756A>G, rs1805087), and methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1 (gene <i>MTHFD1</i> 1958G>A, rs2236225)—well-studied functional variants involved in one-carbon metabolism—and gynecologic cancer risk, and the interaction between these polymorphisms and depression. A total of 200 gynecologic cancer cases and 240 healthy controls were recruited to participate in this study. Three single-nucleotide variants (SNVs) (rs1801133, rs1805087, rs2236225) were genotyped using the PCR-restriction fragment length polymorphism method. Depression was assessed in all patients using the Hamilton Depression Scale. Depression was statistically significantly more frequent in women with gynecologic cancers (69.5% vs. 34.2% in controls, <i>p</i> < 0.001). <i>MTHFD1</i> rs2236225 was associated with an increased risk of gynecologic cancers (in dominant OR = 1.53, <i>p</i> = 0.033, and in log-additive models OR = 1.37, <i>p</i> = 0.024). Moreover, an association was found between depression risk and <i>MTHFR</i> rs1801133 genotypes in the controls but not in women with gynecologic cancers (in codominant model CC vs. TT: OR = 3.39, 95%: 1.49–7.74, <i>p</i> = 0.011). Cancers of the female reproductive system are associated with the occurrence of depression, and ovarian cancer may be associated with the rs2236225 variant of the <i>MTHFD1</i> gene. In addition, in healthy aging women in the Polish population, the rs1801133 variant of the <i>MTHFR</i> gene is associated with depression.