<p>Leptospirosis is a zoonotic disease caused by infectious bacteria in the genus <i>Leptospira</i>. The disease is a common public health and veterinary problem worldwide due to the impaired reproductive ability of the affected cattle. This study builds on our previous work on the leptospirosis transmission for cattle and turns it into a non-autonomous problem to investigate the optimal control measures and resolve the health and economic losses. It does this by looking at the costs and benefits of three time-dependent actions: prevention, vaccination, and treatment. The characterization of optimality systems was analytically studied using Pontryagin’s minimum principle. For various control strategies, numerical simulations of the optimality system were run using the GEKKO dynamic optimization suite in the Python program. The results, both with and without controls, were graphically shown. According to the numerical results, a combination of prevention, vaccination, and treatment measures could significantly reduce the risk of leptospirosis outbreaks in cattle herds more than the application of a single control measure. In addition, a cost-effectiveness analysis was conducted to identify the most cost-effective approach utilizing incremental and average cost-effectiveness ratios. Accordingly, we found that when resources are scarce, the vaccination-only approach is the most economical way to control the spread of leptospirosis.</p>