Introduction/Background The steadily increasing bacterial resistance to existing antimicrobial drugs is a significant issue, hence, it is imperative to look out for new approaches to bacterial therapy Occasionally, effective inhibitory action is not produced when antibiotics are used alone. To overcome this problem, a combination of drugs is often used. One approach to treat infectious diseases is the use of a combination of antibiotics together with plant extracts or phytochemicals. For patients with serious infections caused by pathogens resistant to drugs, combination therapy is beneficial and useful. Materials and Methods Seven antibiotics were obtained from a local pharmacy (gentamicin, ceftazidime, ciprofloxacin, doxycycline, amoxicillin, ceftriaxone, and azithromycin). Minimum inhibitory concentrations (MIC) were determined by broth micro-dilution method, and different antimicrobial combinations were studied on 20 Multidrug-resistant (MDR) clinical isolates (10 S. aureus and 10 P. aeruginosa). Moreover, the antibacterial activity of some volatile oils (limonene, rosemary, salvia, thymus, and black pepper), plant extracts (moringa seed, curcumin, and capsicum), and phytochemicals (thymol, and chitosan) was detected against S. aureus and P. aeruginosa isolates using broth micro-dilution method. Results According to our findings, ceftriaxone and ciprofloxacin or gentamicin together exhibited a substantial synergistic effect against S. aureus. Moreover, the combination of amoxicillin with ceftazidime was synergistic to reduce MIC by five to six times. Regarding MDR clinical isolates of P. aeruginosa, the combination of azithromycin with doxycycline exhibited a decrease of MIC of azithromycin by about five to sixfold. The combination of gentamicin with ceftriaxone was significant. For natural compounds, thymol, rosemary oil, curcumin, capsicum, and moringa seed extract exhibited the highest synergistic activity with the tested antibiotics against S. aureus and P. aeruginosa. Conclusion In conclusion, the lack of new antibiotics necessitates the improvement of existing ones. Our study shows that antibiotic combinations and antibiotic-natural plant combinations are very promising strategies for combating complex bacterial resistance.