The job effectiveness of employees has received significant attention in workplace studies. This is due to the general recognition that this variable can be a major determinant of an organizational working system. The fact that job effectiveness among academic staff in the College of Education may have an impact on institutional quality performance necessitates that closer attention be paid to factors such as organizational culture, work ethics, and spouse relations as potent variables that could influence job effectiveness. This study therefore examined organisational culture, work ethics, and spouse relations as determinants of job effectiveness of academic staff in Colleges of Education in South West, Nigeria. It also looked at the moderating influence of gender, age, and academic qualification on the predictive powers of the independent variables on academic staff job effectiveness. This study adopted a survey research design of ex-post facto type. A sample of 1,146 married academic staff was selected through the multistage sampling technique from a population of 2,898 academic staff in Colleges of Education in South-West, Nigeria. Three research questions and eight hypotheses were answered and tested respectively to guide the study. Four validated instruments were used for data collection; LJEQ (?=0.82), OCQ (?=0.75), LWERS (?=0.78), and WPAT (?=0.78). Data were analyzed using descriptive statistics, Pearson Product Moment Correlation, Multiple Regression Analysis, t-test, and analysis of Variance (ANOVA) at 0.05 level of significance. Findings revealed, among other things, that to some extent, the level of academic staff job effectiveness was very high in Colleges of Education. The finding further showed that organizational culture, work ethics, and spouse relations significantly predicted academic staff job effectiveness in Colleges of Education (F(3, 1017) = 58.672, p < .05). It was recommended among others that the management of colleges should continuously carry out regular appraisals to determine the level of job effectiveness of the staff and invest in capacity development through training and retreats to align staff with organizational culture and work ethics of the institution.