Background. Postpartum depression is a serious mental health issue linked to maternal morbidity and negative effects for infant’s normal growth, development, and well-being. This study is aimed at assessing the prevalence and factors associated with postpartum depression among mothers attending a tertiary hospital in Nepal. Methods. A hospital-based cross-sectional study was conducted among 173 postpartum mothers (<6 weeks postdelivery) who were receiving care either at the postnatal ward or immunization clinic of Universal College of Medical Sciences and Teaching Hospital in Bhairahawa, Rupandehi district, Nepal. The study was carried out from October 2020 to February 2021 by using purposive sampling technique for selecting respondents. The variables that showed significant association with the dependent variable having
p
value < 0.05 in bivariate analysis were entered into multivariate logistic regression model to find the final associated factors. Results. The prevalence of postpartum depression was 20.2% among mothers attending a tertiary hospital in Nepal. The mean age of the respondents was
24.77
±
3.47
. Factors such as mothers having female child (
AOR
=
6.39
,
CI
=
1.54
−
26.46
), unplanned pregnancy (
AOR
=
10.08
,
CI
=
2.91
−
34.94
), pregnancy-induced health problems (
AOR
=
9.68
, CI: 3.51-26.64) were associated with an increased risk of postpartum depression. Similarly, mothers having formal education (
AOR
=
0.28
, CI: 0.08-0.91), whose spouses have secondary and above education (
AOR
=
0.16
, CI: 0.03-0.85), and who have ≥4 ANC visits (
AOR
=
0.15
,
CI
=
0.05
−
0.40
) were significantly associated but have a protective effect with postpartum depression. Conclusions. Sex of newborn, mother’s and spouse’s education, intention of pregnancy, ANC visits, and pregnancy-induced health problems were found to be significantly associated with postpartum depression. Hence, specific health education program regarding maternal and child health integrating mental health should be provided to pregnant women, mothers, and their husbands, focusing on gender discrimination. Similarly specific orientation program should be provided to local health worker about the importance of planned pregnancy, in order to reduce pregnancy related health problems during ANC visits and to mothers after their delivery to reduce further chances of postpartum depression.