Background: Venous thrombosis is a common life-threatening disorder and is a significant source of morbidity and mortality in hospitalized patients. This study aims to evaluate soluble P-selectin (sP-Sel) and to correlate with D-dimer and C-reactive protein (CRP) in venous thrombosis patients. Subjects and Methods: This cross-sectional study includes 144 subjects, with cases (100) as duplex scan positive, Control A (22) includes age matched with no signs of inflammation, and Control B (22) with age matched with signs of inflammation and duplex scan negative. The severity of venous thrombosis is assessed by Well’s score. The statistical analysis was performed using Microsoft Excel, GraphPad Prism version 9.4.1 (681), and MedCalC 20.114. Normality for all the variables in controls and cases was checked. The data were expressed as the median (interquartile range). Comparison between groups was made using the Kruskal–Wallis test. Post hoc analysis was conducted using Dunn’s multiple comparison tests. Quantitative correlation of data was done using Spearman rho test. Receiver operating characteristics curves were constructed to assess the diagnostic performance of sP-Sel, and cutoff value was established. Linear and logistic regression analyses were also performed to predict the disease outcome. Results: In the study, controls have more females, but cases turned out to be more in males may be due to additional risk factors such as smoking and alcohol associated with diabetes mellitus and hypertension. The D-dimer (ng/mL) levels were compared in Control A, B, and cases, and the values were 67.5 (36–107), 135 (101–264), and 1309 (750–2390) ng/mL, respectively, and were statistically significant (P < 0.0001). The sP-Sel (ng/mL) were compared in Control A, B, and cases; the values were 7.59 (7.150–10.64), 7.84 (7.0–11.87), and 19.64 (12.95–33.29), respectively, and were statistically significant (P < 0.0001). Based on the Well’s score, the cases were categorized into having low disease probability, moderate probability, and high probability, and the sP-Sel is high in cases with high probability and is statistically significant. Based on CRP (mg/L) positive (>6 mg/L) or negative (<6 mg/L), the D-dimer was statistically significant with CRP positive group, i.e. 2900 (1643–4159). sP-Sel at a cutoff of >14.29 (ng/mL) showed a sensitivity of 70% and specificity of 81.8% positively predicting the diagnosis of venous thrombosis and D-dimer at a cutoff of >367 ng/mL with a sensitivity of 91% and specificity of 95.45% is positively predicting the diagnosis of venous thrombosis. When multilinear regression analysis was performed D-dimer (ng/mL) and Well’s score were positively associated with sP-Sel (ng/mL) in cases of venous thrombosis. Logistic regression analysis is applied sP-Sel (ng/mL), D-dimer (ng/mL), Well’s score, and smoking came out as the positive predictor for the occurrence of venous thrombosis. Conclusion: D-dimer and Well’s scores are positively associated with sP-Sel and help to diagnose venous thrombosis.