This study aimed at assessing the predictors of knowledge about the Maternal and Perinatal Deaths Surveillance and Response (MPDSR) system among health workers in the Morogoro region. It was an analytical cross-sectional study, conducted from April 27 to May 29, 2020. A multistage sampling technique was used to recruit 360 health workers. A semi-structured questionnaire was used to collect the data. Statistical Package for Social Science (SPSS v.20) software was used for data entry and analysis. Bivariate and multivariate logistic regression analyses were used to assess factors associated with knowledge of MPDSR. A total of 105 (29.2%) health workers in the Morogoro region had adequate knowledge of the MPDSR system. After controlling for confounders, predictors of knowledge on the MPDSR system were the level of health facility a health worker was working (n [hospital [adjusted odds ratio [AOR] = 2.668 at 95% confidence intervals [CI] = 1.497–4.753, P = .001]), level of education of a health worker (diploma [AOR = 0.146 at 95% CI = 0.038–0.561, P = .005]), and status of training on MPDSR (trained [AOR = 7.253 at 95% CI = 3.862–13.621, P ≤ .001]). The proportion of health workers with adequate knowledge about the MPDSR system in the Morogoro region is unacceptably low. Factors associated with adequate knowledge were those working in hospitals with higher levels of professional training and those who had ever had training in MPDSR. A cost-effective strategy to improve the level of knowledge regarding MPDSR in this region is highly recommended.