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Aims/Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and neovascularization. Reliable biomarkers for monitoring RA activity are needed to optimize treatment strategies. Periostin (POSTN) and vascular endothelial growth factor (VEGF) contribute to tissue remodeling and angiogenesis in various diseases, but their combined role and clinical significance in RA remain underexplored. This study aimed to evaluate serum POSTN and VEGF levels in RA patients and their correlation with disease activity. Methods Serum levels of POSTN and VEGF were quantified using enzyme-linked immunosorbent assay (ELISA) in 86 RA patients, 36 osteoarthritis (OA) patients, and 40 healthy volunteers (HV) enrolled between January 2022 and December 2024 at Jinhua Municipal Central Hospital. RA patients were categorized into active (Disease Activity Score-28 [DAS28] >2.6) and stable (DAS28 ≤2.6) subgroups. Serum POSTN and VEGF levels were compared across the three study groups and between RA activity subgroups. Correlations between these biomarkers and clinical/laboratory parameters, including DAS28, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), were analyzed. Results Serum POSTN and VEGF levels were significantly higher in RA patients [(125.21 ± 35.17) ng/mL, (106.45 ± 29.54) pg/mL] compared to OA patients [(98.41 ± 30.09) ng/mL, (82.28 ± 23.18) pg/mL] and healthy controls [(75.86 ± 22.81) ng/mL, (71.24 ± 11.72) pg/mL] (all p < 0.001). Furthermore, POSTN and VEGF levels in the active RA group [(144.68 ± 29.98) ng/mL, (121.75 ± 27.49) pg/mL] were significantly higher than those in the inactive group [(100.62 ± 24.23) ng/mL, (87.33 ± 19.12) pg/mL] (all p < 0.001). Spearman's or Pearson's correlation analyses revealed a positive correlation between POSTN and VEGF in RA patients (r = 0.708, p < 0.001). Serum POSTN levels were positively correlated with DAS28, CRP, and ESR (r_DAS28 = 0.753, r_CRP = 0.623, r_ESR = 0.437, p < 0.001) so was VEGF (r_DAS28 = 0.720, r_CRP = 0.433, r_ESR = 0.623, all p < 0.001). Conclusion POSTN and VEGF levels are elevated in RA patients, correlate with disease activity markers, and may serve as complementary biomarkers for assessing RA activity.