Background: Postpartum depression (PPD) is a major maternal mental-health problem with significant consequences for both mother and infant. Prevalence in India varies widely, with higher rates reported in southern states. Limited data are available from northern Karnataka, particularly Kalaburagi, despite regional socioeconomic vulnerabilities. Therefore, the present was undertaken to estimate the prevalence of postpartum depression and identify associated sociodemographic, obstetric, neonatal, and psychosocial determinants among mothers attending the immunisation clinic of a tertiary care centre in Kalaburagi. Methods: An analytical cross-sectional study was conducted among 380 postpartum mothers using systematic random sampling. Data were collected through a pre-tested questionnaire and the Edinburgh Postnatal Depression Scale (EPDS). A cutoff score of ≥13 identified probable PPD. Associations were examined using Chi-square tests, and significant variables (p < 0.20) were included in multivariable logistic regression. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) were computed. Results: The prevalence of probable PPD was 29.2%, while 28.4% had possible depression (EPDS 8–12). Lower education (45.3% vs. 18.7%), low socioeconomic status (40.6% vs. 20.9%), unwanted pregnancy (52.0% vs. 20.9%), infant illness (47.0% vs. 24.2%), husband’s alcohol use (46.8% vs. 16.9%), low family support (50.4% vs. 17.7%), poor marital relationship (53.9% vs. 12.8%), and family conflict (45.1% vs. 17.4%) were significantly associated with PPD (p < .05). In multivariable analysis, key predictors included low socioeconomic status (AOR 2.36, 95% CI: 1.31–4.24), unwanted pregnancy (AOR 3.12, 1.77–5.48), infant illness (AOR 2.09, 1.15–3.78), and low family support (AOR 3.58, 2.06–6.23). Conclusion: Socioeconomic vulnerability, unintended pregnancy, neonatal illness, and inadequate family support are major determinants. Incorporating routine PPD screening into immunisation clinics and strengthening family-centered psychosocial support services are essential for early detection and improved maternal and child health outcomes.