Hyperprolactinemia (HPRL) is a common adverse reaction induced by antipsychotic therapy in patients with schizophrenia, which greatly undermines medication adherence and impairs physiological functions of multiple body systems. In this real-world study, we analyzed retrospective prolactin testing data to compare the incidence of HPRL between schizophrenia patients and patients with other psychiatric disorders, so as to identify clinical high-risk factors. Meanwhile, hormones including thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), free triiodothyronine (FT3), tetraiodothyronine (T4), Triiodothyronine (T3), and estradiol that closely correlated with prolactin metabolism were also included in the analysis. The results indicated that female patients with schizophrenia had the highest risk of HPRL (19.31%, n = 2009), and women during the prime reproductive (25–40 years) showed the highest average prolactin concentration (1,389.22 ± 50.138 mIU/L, n = 966). Distinct antipsychotics usage rates were observed among different clinical subgroups. Risperidone, paliperidone and sulpiride showed an increasing trend with elevated PRL levels, whereas quetiapine and aripiprazole were more frequently prescribed in the low-risk HPRL group. Antipsychotics showed divergent dopamine D2/D3 and 5-HT2A receptor-binding affinities (Ki values), and we constructed a weighted multi-receptor affinity index that demonstrated a strong linear correlation with the PRL risk score (R2 = 0.878). Additionally, the average incidence of extrapyramidal symptoms (EPS) increased with rising PRL levels (P = 2.24E-10). Further analysis of EPS risk revealed distinct safety profiles across antipsychotics, with aripiprazole—characterized by low HPRL liability—demonstrating a higher EPS risk. The severe HPRL group presented a tendency of decreased thyroid function (TSH, P = 0.0027; FT4, P = 0.000031; FT3, P = 0.0076; T4, P = 0.0025) and a significant reduction in estradiol levels (P = 0.000049). Based on homogeneous clinical real-world data, this study comprehensively evaluated multiple antipsychotic medications simultaneously. It provides empirical clinical evidence for individualized medication strategies in patients with comorbid HPRL and EPS, and offers real-world evidence for the clinical early risk recognition, and long-term medication decision-making among patients with multiple adverse reactions concurrently.