Purpose Trichinellosis affects around 11 million people globally. Treatments for this medical condition are limited by adverse effects and resistance, emphasising the importance of effective and safe therapies. Consequentially, we sought to study colchicine’s synergistic effects with atorvastatin or acetazolamide in the treatment of Trichinella spiralis (T. spiralis) infected mice. Methods Seventy mice were evenly divided into two groups (a and b) of 35 each. During the intestinal phase, group (a) began therapy on the second day post-infection (dpi) and lasted four days. Group (b) had treatment for four weeks during the muscle phase, beginning on the 12th dpi. While the other five infected groups received atorvastatin, colchicine, acetazol amide, a combination of acetazolamide and colchicine, or none, one group of infected mice received no treatment at all as a negative control. The efficacy was assessed by parasite count, histopathology and scanning electron microscopy. Results Our data revealed that the combination treatment lowered T. spiralis adult worm and larvae counts in infected ani mals. Moreover, it restored the normal intestinal and muscular architecture, reduced edema, and alleviated inflammation, as demonstrated by reduced inflammatory infiltrate. Scanning electron microscopic examination of adults and larvae verified our findings. Conclusion Adjuvant treatment with colchicine as an antifibrotic can help treat muscle trichinellosis by reducing the produc tion of fibrous tissue. This might help to enhance treatment results by enabling the admission of larvicidal medications and, as a result, reducing the number of larvae in the muscle, which together form the basis of pathology and can be debilitating for the patient.