Background: Little is known about risk factors for sick building symptoms (SBS) among health care workers (HCWs) who often face the workload, exposure to chemicals, and biological contaminants in the workplace. This study aims to evaluate the correlation between SBS and the symptoms among HCWs. Methods: A total of 207 HCWs were recruited in a large hospital-based cross-sectional survey between March and June 2017, southern Vietnam. Face-to-face interviews were conducted for collecting data on demographics, SBS-related symptoms, working environments, and conditions. Indoor environmental conditions were measured. SBS scores, ranging from 0 to 24, were determined by a sum of the scores of general symptoms, mucosal irritation, and skin symptoms; multivariate regression analyses and the Lindeman, Merenda, and Gold (LMG) test were used to investigate the predictors and its impact on the SBS. Results: A mean SBS score was 9.7 (range: 1–21). Compared with males, females were more likely to report higher SBS scores (10.2 vs. 7.9, p < 0.001). Being female, atopy, varying temperature room, stuffy “bad” air dust, and dirt had higher SBS scores of 2.0; 1.8; 1.7; 1.9; 3.8, respectively. LMG test showed that dust and dirt, and stuffy “bad” air were the predominant risk factors for SBS. Conclusions: Our study reveals that working conditions are important and significantly associated with SBS. Taken together with our findings, the working condition criteria approach trained for architects, builders, owners, and maintenance of the building is highly recommended for indoor air quality improvement. Furthermore, larger-sample studies about working condition are urgently needed to better manage SBS.