The study investigated work meaningfulness and sense of responsibility as correlates of work performance of Head of Departments of Federal Universities in South-South Zone, Nigeria. Two research questions were answered while two null hypotheses were tested at 0.05 alpha level. The study adopted a correlation design. The population for the study was 378 HoDs in 378 Departments in six Federal Universities in South-South, Nigeria. The sample size was 310 HoDs representing 82.01% of the population. Two self-designed instruments titled Work Meaningfulness and Sense of Responsibility Scale (WMSRS) and Work Performance scale (WPS) were used for data collection. Face and content validities were ensured by experts in Measurement and Evaluation. Simple regression was used to answer the research questions while t-test associated with simple regression was used to test the null hypotheses at 0.05. It was found among others that work meaningfulness significantly predicted work performance among HoDs of federal universities in South-South Zone, Nigeria while sense of responsibility did not. It was recommended that the Heads of Departments should value and approach their job with achievement drive in order to effectively make use of their multiple skills. The principal officers in the university should clearly spell out the job responsibilities of the HoDs in their various units and departments in order to encourage job autonomy.