This study aimed to analyze the epidemiological characteristics of cleft lip and/or palate (CL/P) and CL/P-related perinatal deaths, provide some information for intervention programs to reduce the incidence of CL/P and provide clues for future researchers. Data were obtained from the Birth Defects Surveillance System in Hunan Province, China, 2016–2020. Incidences of CL/P [number of cases per 1000 fetuses (births and deaths at 28 weeks of gestation and beyond)] with 95% confidence intervals (CI) were calculated by residence, gender, maternal age, year, and major types [cleft lip only (CL), cleft palate only (CP), and cleft lip with palate (CLP)]. Crude odds ratios (ORs) were calculated to examine the association of each maternal characteristic with CL/P. Pearson chi-square tests (χ2) were used to examine the association of each maternal characteristic with CL/P-related perinatal deaths. A total of 847,755 fetuses were registered, and 14,459 birth defects were identified, including 685 CL/P (accounted for 4.74% of all birth defects). CL, CP, and CLP accounted for 24.67% (169 cases), 36.79% (252 cases), and 38.54% (264 cases) of all CL/P, respectively. The incidence of CL/P was 0.81‰ (95%CI 0.75–0.87). The incidence of CL was 0.20‰ (95%CI 0.17–0.23) (169 cases), of CP was 0.30‰ (95%CI 0.26–0.33) (252 cases), and of CLP was 0.31‰ (95%CI 0.27–0.35) (264 cases). CL was more common in males than females (0.24‰ vs. 0.15‰, OR = 1.62, 95%CI 1.18–2.22). CP was more common in urban than rural (0.36‰ vs. 0.25‰, OR = 1.43, 95%CI 1.12–1.83), and less common in males than females (0.22‰ vs. 0.38‰, OR = 0.59, 95%CI 0.46–0.75). CLP was more common in males than females (0.35‰ vs. 0.26‰, OR = 1.36, 95%CI 1.06–1.74). Compared to mothers 25–29 years old, mothers < 20 years old were risk factors for CLP (OR = 3.62, 95%CI 2.07–6.33) and CL/P (OR = 1.80, 95%CI 1.13–2.86), and mothers ≥ 35 years old was a risk factor for CLP (OR = 1.43, 95%CI 1.01–2.02). CL/P-related perinatal deaths accounted for 24.96% (171/685) of all CL/P, of which 90.64% (155/171) were terminations of pregnancy. Rural residents, low income, low maternal age, and early prenatal diagnosis are risk factors for perinatal death. In conclusion, we found that CP was more common in urban areas and females, CL and CLP were more common in males, and CL/P was more common in mothers < 20 or ≥ 35 years old. In addition, most CL/P-related perinatal deaths were terminations of pregnancy. CL/P-related perinatal deaths were more common in rural areas, and the proportion of CL/P-related perinatal deaths decreased with the increase in maternal age, parity, and per-capita annual income. Several mechanisms have been proposed to explain these phenomena. Our study is the first systematic research on CL/P and CL/P-related perinatal deaths based on birth defects surveillance. It is significant for intervention programs to prevent CL/P and CL/P-related perinatal deaths. As well, more epidemiological characteristics of CL/P (such as the location of CL/P) and approaches to reduce CL/P-related perinatal deaths need to be studied in the future.