Aquaculture is seen as an essential food-producing sector for improving global food security and nutrition indices. This cross-sectional study examined the health complaints and mental health status of aquaculture workers, as well as their relationship with quality of life, with respect to the brackish water and freshwater aquaculture cultivation system in Penang, Malaysia. The workers’ health complaints were collected, and mental health status was evaluated as means of depression, anxiety, stress and self-esteem. Self-perceived quality of life was assessed using a structured questionnaire. This study involved the participation of 88 brackish water (84.6%) and 16 freshwater (15.4%) aquaculture workers. A total of 72.7% of the brackish water aquaculture workers were aged beyond 50 years old and had worked within five years (77.3%) in the aquaculture industry. Both brackish water and freshwater cultivation workers were confronted with fatigue, pain and insomnia. Up to 48%, 40.4%, 26% and 24% of them were facing depression, anxiety, stress and low self-esteem, respectively. A total of 3.4% of the brackish water aquaculture workers were having bad quality of life. The complaints of neck/shoulder/arm pain (F = 13.963; p < 0.001), back pain (F = 10.974; p < 0.01), hand/wrist pain (F = 8.041; p < 0.01), knee/hip pain (F = 12.910; p < 0.01) and insomnia (F = 10.936; p < 0.01) were correlated with bad quality of life among the workers. For mental health status, self-esteem (F = 4.157; p < 0.05) was found to be negatively correlated with quality of life scores. The results outlined the concerning level of health complaints and psychological distress among the aquaculture workers. The study emphasized the importance of developing an appropriate occupational health strategy in the aquaculture industry. Longitudinal investigations aimed to explore the effects of psychological distress on employment productivity among the high-risk workers are warranted.