Abstract Introduction Pulmonary infections are frequent in immunocompromised hosts (ICH), and microbial detection is difficult. As a new method, next‐generation sequencing (NGS) may offer a solution. Objectives This study aimed to assess the impact of NGS‐assisted pathogenic detection on the diagnosis, treatment, and outcomes of ICH complicated by pulmonary infection and radiographic evidence of bilateral diffuse lesions. Methods This study enrolled 356 patients with ICH complicated by pulmonary infection that were admitted to Zhongshan Hospital, Fudan University, from November 17, 2017, to November 23, 2018, including 102 and 254 in the NGS and non‐NGS groups, respectively. Clinical characteristics, detection time, rough positive rate, effective positive rate, impact on anti‐infective treatment plan, 30‐day/60‐day mortality, and in‐hospital mortality were compared. Results NGS‐assisted pathogenic detection reduced detection time (28.2 h [interquartile range (IQR) 25.9–29.83 h] vs. 50.50 h [IQR 47.90–90.91 h], P < 0.001), increased positive rate, rate of mixed infection detected, effective positive rate, and proportion of antibiotic treatment modification (45.28% vs. 89.22%, 4.72% vs. 51.96%, 21.65% vs. 64.71%, 16.54% vs. 46.08%, P < 0.001). The NGS group had a significantly lower 60‐day mortality rate (18.63% vs. 33.07%, P = 0.007). The difference in the Kaplan–Meier survival curve was significant (P = 0.029). After multivariate logistic regression, NGS‐assisted pathogenic detection remained a significant predictor of survival (OR 0.189, confidence interval [CI], 0.068–0.526). Conclusion NGS‐assisted pathogenic detection may improve detection efficiency and is associated with better clinical outcomes in these patients.