This study explored how maternal and infant illness correlated with the risk of postpartum depression in the Chinese Qinba Mountains region. In total, 131 villages comprising 435 families with infants (≤6 months old) were randomly sampled. We collected data on maternal and infant illnesses and maternal health knowledge level. The Depression, Anxiety, and Stress Scale-21 was used to measure the risk of postpartum depression. We used descriptive statistics and multivariate logistic regression for the analysis. Infant overall health status was a risk factor for postpartum depression (odds ratio (OR) = 1.90, 95% Confidence Interval (95% CI) = 1.10~3.28), whereas maternal overall health status was not correlated with postpartum depression (OR = 1.36, 95% CI = 0.55~3.39). For specific illnesses, infants experiencing over two common illnesses in the past two weeks (OR = 1.98, 95% CI = 1.13~3.45) and mothers experiencing over two common pains within two weeks after delivery (OR = 1.77, 95% CI = 1.02~3.08) were risk factors for postpartum depression, whereas infants with mild and severe stunted growth, maternal C-section, and postpartum body mass index (normal or overweight) were not correlated with it (all p > 0.050). Maternal health knowledge was an important moderator of maternal and infant illnesses on the risk of postpartum depression. In conclusion, maternal and infant illness were essential factors for the risk of postpartum depression in a poor rural region in western China, which may be mainly affected by the feeling of uncertainty of illness. Improved maternal and infant health and enhanced maternal health knowledge might alleviate the risk of postpartum depression.