Background Depression is a global public health problem. Studies show comorbid depression increases morbidity, mortality, and associated risk of poor adherence compared to those without depression. Materials and Method An analytical cross-sectional study was conducted among 326 patients who met the inclusion criteria. They were selected following simple random sampling from medical OPD and ward of Shree Birendra Hospital Kathmandu, Nepal. Semi-structured interview schedule (SSIS), Beck Depression Inventory-II (BDI-II), and Kuppuswamy’s Scale (KS) were used for data collection. Data analysis was done using SPSS version 26 and STATA version 15. Simple frequency distribution of attributes presented in tables and association assessed using Chi-square/ Fisher’s exact test. Further, the relation between depression and other independent factors is quantified using multivariate/ multivariable logistics regression analyses. Result Using Beck depression inventory (BDI-II) as a tool to determine depression 52.1% (n=170) had minimal or no depression, 16.9% (n=55) had mild depression, 18.7 %( n=61) had moderate depression and 12.3% (n=40) had severe depression i.e. 47.9% of population had some form of depression. Prevalence of depression among patient with single comorbidity found to be 30.9% (n=25, N=81) for hypertension, 43.3% (n=13, N=30) for diabetes mellitus, 45.6% (n=31, N=68) for chronic obstructive pulmonary disease, 77.5% (n=31, N=40) for chronic kidney disease, and 60 %( n=9, N=15) for chronic heart disease. Depression among patient with multiple comorbidities (more than one disease above mention) was found to be 51.1% (n=47, N=92). Prevalence of depression was more among patients with history of longer duration of illness; 11 years and above 52.9 % (n=36, N=68); 6-10 years 48.3 % (n=43, N=89); 1-5 years 45.6 %( n=77, N=169). Conclusion This study showed that the prevalence of depression has a significant relationship with the duration of illness. Therefore, early recognition and treatment play a crucial role in reducing the effects of depression.