Objective. To evaluate the value of combined detection of serum CA125, CA199, and HE4 in the diagnosis of ovarian cancer. Methods. Relevant articles retrieved from PubMed, Elsevier Science, Springer, China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases were screened strictly according to inclusion and exclusion criteria. Included literature published from January 2005 to December 2021. (2) Serum HE4, CA125, CA199, and their combination for ovarian cancer diagnostic tests were studied, and healthy subjects or patients with the benign disease were taken as a control group. (3) Pathological tissue diagnosis as the gold standard. (4) Complete original data can be obtained. (5) The sample size was ≥20. (6) Language is limited to Chinese and English. Data features and QUADAS table were extracted from the included literature, and QUADAS evaluation tool detail table was used for the included study. Conduct quality evaluation. Statistical analysis was carried out using meta-disc software version 1.4. Appropriate effect model was selected to merge the effect size, and the forest maps of merge sensitivity, merge specificity, and merge likelihood ratio were obtained. Results. The results of meta-analysis showed that there was a statistical difference in diagnostic specificity analysis of CA125 (
OR
=
1.91
, 95% CI (1.58, 2.32),
P
<
0.00001
,
I
2
=
67
%
,
Z
=
6.58
); diagnostic sensitivity analysis of CA125 (
OR
=
2.50
, 95% CI (1.73, 3.62),
P
<
0.00001
,
I
2
=
0
%
,
Z
=
4.90
); diagnostic specificity analysis of CA199 (
OR
=
1.98
, 95% CI (1.60, 2.44),
P
<
0.00001
,
I
2
=
89
%
,
Z
=
6.35
); diagnostic sensitivity analysis of CA199 (
OR
=
1.92
, 95% CI (1.46, 2.52),
P
<
0.00001
,
I
2
=
73
%
,
Z
=
4.70
); diagnostic specificity analysis of HE4 (
OR
=
2.08
, 95% CI (1.65, 2.63),
P
<
0.00001
,
I
2
=
73
%
,
Z
=
6.19
); diagnostic sensitivity analysis of HE4 (
OR
=
2.37
, 95% CI (1.87, 3.00),
P
<
0.00001
,
I
2
=
83
%
,
Z
=
7.19
). Conclusion. In the clinical assisted diagnosis of ovarian cancer, combined detection of CA125, CA199, and HE4 has the stronger discriminant ability and higher accuracy than single detection of CA125, which can improve the diagnostic efficiency.